Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

This application claims priority to U.S. Provisional Application Ser.No. 61/348,422 filed May 26, 2010, which is incorporated by-reference inits entirety.

FIELD OF THE INVENTION

This invention pertains to water soluble compounds which inhibit theactivity of Bcl-2 anti-apoptotic proteins, compositions containing thecompounds, and methods of treating diseases during which anti-apoptoticBcl-2 proteins are expressed.

BACKGROUND OF THE INVENTION

Anti-apoptotic Bcl-2 proteins are associated with a number of diseases.There is therefore an existing need in the therapeutic arts forcompounds which inhibit the activity of anti-apoptotic Bcl-2 proteins.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, spleen cancer, and the like is described incommonly-owned PCT U.S. 2004/36770, published as WO 2005/049593, and PCTU.S. 2004/37911, published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2063, 3, 378-384:British Journal of Haematology 2000, 110(3), 584-90: Blood 2000 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned U.S. Provisional Patent Application Ser. No. 60/988,479.Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

Solubility influences the oral absorption of pharmaceuticals. Drugs withpoor dissolution rates are associated with low and variablebioavailability, higher potential for food effects, and inability todeliver high doses for toxicity studies, and difficulty in developingparenteral formulations. Therefore, increasing the solubility ofcompounds may alleviate these risks associated with low solubility and,moreover, constitute an advantage.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salt, which are useful as selectiveinhibitors of one or more than one anti-apoptotic protein family member,the compounds having Formula (I), (II), or (III)

wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂or C(O)OR^(A):

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO-R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)NHR¹, NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹,NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂,NHSO₂R¹, NR¹SO₂R¹, NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R)¹(₂, C(O)NHNOH,C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹,NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H.CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂. C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃) CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A);

E¹ is H, R¹.OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂N₃, OH, C(O)H, CHNOH, CH(NOCH₃),CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹²,OR¹⁷, C(O)R¹³, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with S(O)₂(OH), C(O)OROP(O)(OH)(OH),C(O)ROP(O)(OH)(OH), C(O)NH(R ⁴⁰)NH₂, C(O)R⁴⁰C(O)NR⁵⁰; ORP(O)(OH)(OH),OP(O)(OH)(OH), or OC(O)CH₂OP(O)(OH)(OH);

R¹ and R^(1B), are each independently R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkenyl:

R² is phenyl which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶ is alkyl, alkenyl or alkynyl, each of which is independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three independently selected R⁶, NC(R^(6A))(R^(6B)),R⁶, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷), C(O)R⁷, C(O)NH₂, C(O)NHR³,NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₇, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NH₂,NHC(O)NHR⁷, NHC(O)CH(CH₂)NHC(O)CH(CH₃)NH₂, NHC(O)(CH₃)NHC(O)CH(CH₃)NHR¹,OH, (O), C(O)OH, (O), N₃, CN, NH₂,CF₃, CF₂CF₂, F, Cl, Br or Isubstituents;

R⁶ is C₃-C₄-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₁, CF₆-CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₁)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₄-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₂, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is on unfused or fused with benzene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)(₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₇, OH, (O), C(O)OH, N₁,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or 1 substitutents:

R¹² is R¹¹, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with benzene, heteroarene orR^(13A); R^(18A) is cycloalkane, cycloalkene, heterocyloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with benzene,heteroarene or R^(13A); R^(13A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene orR^(15A):R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀- cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R₂₂, OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, C(O)N(R²²)₂, OH, (O),C(O)OH, N₃, CN, CF₁, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²², R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁸ is heteroarene which is unfused or fused with benzene, heteroareneor R²⁴A; R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene:

R²⁴ is C₃-C₆-cycloalkyl or C₄-C₆- cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(25A) ; R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene:

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(30A) ; R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein R³⁰ is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁹, SO₁R³⁷, NHR³⁷ orN(R³²)R³⁷:

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₄ spiroalkyl;

R³² is R³³, C(O)R³³, or C(O)OR³³;

R³³ is R³¹ or R³⁵;

R³⁴ is phenyl which is unfused or fused with benzene, heteroarene, orR^(34A); R^(34A) is cycloakane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene. heterocycloalkane orheterocycloalkene:

R³⁷ is R³⁸, R³⁹ or R⁴¹, each of which is substituted with F, Cl, Br, I,R⁴³, OR⁴¹ , NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is un used or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ C₁-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴² , R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycoalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄C₇-cycloalkenyl, each having one or two Ch₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH d one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁴ is phenyl which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH; moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH, S, SC(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R², R^(2A), R³, R^(3A), R⁴, R^(4A),R⁸, R^(6C), R⁸, R⁹, R^(9A), R¹⁰, R^(10A), R¹³, R^(13A), R¹⁴; R^(14A),R¹⁵, R^(15A), R¹⁸, ^(18A), R¹⁹, R^(19A), R²⁰, R^(20A), R²³, R^(23A),R²⁴, R^(24A), R²⁵, R^(25A), R³⁰, R^(36A), R³¹ R^(31A) taken together,R³⁴, R^(34A), R³⁶, R^(36A), R³⁸, R^(38A), R³⁹, R^(39A), R⁴⁰, R^(40A),R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴, R^(44A), R⁴⁷, R^(47A), R⁴⁸, R^(48A),R⁴⁹, and R^(49A) independently unsubstituted, further unsubstituted,substituted or further substituted with one or two or three or four orfive independently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR^(50, NH) ₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂,C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰,C(O)NHSO₂R⁵⁰, C(O)NR⁴⁴SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O), CN , N₃, NO₂,CF₃, CF₂CF₃, OCF₃, OCF₁CF₃, F, Cl, Br OR 1 substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(51B)B ; R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene:

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₁, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, and alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₁-c₈-cycloalkyl or C₄-c₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₃ or NH and one or two CH moieties unreplacedor replaced with N.

In another embodiment of Formula (I), (I), or (III): A¹ is C(A²); and A²is H.

In another embodiment of Formula (I), (II), or (III): A¹ is C(A²); A² isH; and B¹ is OR¹ or NHR¹.

In another embodiment of Formula (I), (II), or (III): A¹ is C(A²); A² isH; B¹ is or¹ or NHR¹; and D¹ is H.

In another embodiment of Formula (I), (II), or (III): A¹ is C(A²); A² isH; B¹ is OR¹ or NHR¹; D¹ is H; and E¹ is H.

In another embodiment of Formula (I), (II), or (II): A¹ is C(A²); A² isH: B¹ is OR¹ or NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₁.

In another embodiment of Formula (I), (II), or(III): A¹ is C(A²); A² isH; B¹ is OR¹ or NHR¹; D¹ is H; E¹ is H; Y¹ is NO₂; and G¹ is R³⁸, OR³⁸,or NHR³⁸; wherein the R³⁸, or a subsequent on R³⁸, is substituted orfurther substituted with OP(O)(OH)(OH).

Still another embodiment pertains to compounds having Formula (I), (II),or (III); which are

(5-{5-(4{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy}-7yl-7H-pyrrolo[2,3-b]pyridin-7yl)methyl)dihydrogen phosphate;

{5-[5-(4-{[2-4-chlorophenyl)-4,4-dimethylcyclohex-1en1-yl]methyl;piperazin-1-yl)2-{[(4-{[(trans-4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo(2,3-b}pyridin-7-yl}methyldihydrogen phosphate;

(5-{5-(4-{[(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1yl)2-[({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7yl)methyldihydrogen phosphate;

3-[(4-{(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-dimethylpropyldihydrogen phosphate;

trans-4-[(4-{[4-{(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenoxy)methyl]cyclohexyl dihydrogenphosphate; and therapeutically acceptable salts, and metabolitesthereof.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chrome lymphocytic leukemia, myeloma, prostate cancer,small cell lung cancer or spleen cancer, said composition comprising anexcipient and a therapeutically effective amount of a compound ofFormula (I), (II), or (III).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (II), or (III).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell longcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of thecompound of Formula (I), (II), or (III) and a therapeutically effectiveamount of one additional therapeutic agent or more than one additionaltherapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letterswith numerical and/or alphabetical superscripts) and may be specificallyembodied.

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof, thus monovalent moieties having morethan one atom are drawn from left to right and are attached throughtheir left ends, and that divalent moieties are also drawn from left toright.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C_(x)-C_(y) alkyl” meansa straight or branched hydrocarbon chain containing at least onecarbon-carbon double bond containing x to y carbon atoms. The term“C₃-C₆ alkenyl” means an alkenyl group containing 3-6 carbon atoms.Representative examples of alkenyl include, but are not limited to,buta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. The term “C_(x)-C_(y) alkylene” means adivalent group derived from a straight or branched hydrocarbon chaincontaining at least one carbon-carbon double bond and containing x to ycarbon atoms. Representative examples of alkenylene include, but are notlimited to, —CH═CH— and —CH₂CH═CH—. The term “alkyl” as used herein,means a straight or branched, saturated hydrocarbon chain containingfrom 1 to 10 carbon atoms. The term “C_(x)-C_(y) alkyl” means a straightor branched chain saturated hydrocarbon containing x to y carbon atoms.For example “C₁-C₆ alkyl” means a straight or branched chain, saturatedhydrocarbon containing 2 to 6 carbon atoms. Representative examples ofalkyl include, but are not limited to, methyl ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylene” means a divalent group derived front a straight orbranched, saturated hydrocarbon chain of 1 to 10 carbon atoms, forexample, of 1 to 4 carbon atoms. The term “C_(x)-C_(y) alkylene” means adivalent group derived from a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₆ alkylene”means a straight or branched chain. saturated hydrocarbon containing 2to 6 carbon atoms. Representative examples of alkylene include, but arenot limited to, —CH_(2—), —CH₂CH_(2—), —CH₂CH₂CH_(2—), —CH₂CH₂CH₂CH_(2—)and —CH₂CH(CH₃)CH_(2—),

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. The term “C_(x)-C_(y) alkynyl”means a straight or branched chain hydrocarbon group containing from xto y carbon atoms. For example “C₃-C₆ alkynyl” means a straight orbranched chain hydrocarbon group containing from 3 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited to, acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkynylene,” as used herein, means a divalent radical derivedfrom a straight or branched chain hydrocarbon group containing from 2 to10 carbon atoms and containing at least one carbon-carbon triple bond.

The term “aryl” as used herein, means phenyl.

The term “cyclic moiety,” as used herein, means benzene, phenyl,phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene,cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl,cycloalkynylene, heteroarene, heteroaryl, heterocycloalkane,heterocycloalkyl, heterocycloalkene, heterocyeloalkenyl and spiroalkyl.

The term “cycloalkylene” or cycloalkenyl” or “cycloalkane” as usedherein, means a monocyclic or bridged hydrocarbon ring system. Themonocyclic cycloalkyl is a carbocyclic ring system containing three toten carbon atoms, zero heteroatoms and zero double bonds. Examples ofmonocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. The monocyclic ring may containone or two alkylene bridges, each consisting of one, two, or threecarbon atoms, each linking two non-adjacent carbon atoms of the ringsystem. Representative examples of such bridged cycloalkyl ring systemsinclude, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3.7)]nonane (octahydro-2.5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3.7)]decane (adamantane). Themonocyclic and bridged cycloalkyl can be attached to the parentmolecular moiety through any substitutable atom contained within thering system.

The terms “cycloalkenylene,” or “cycloalkenyl” or “cycloalkene” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkenyl has four to ten carbon atoms and zeroheteroatoms. The four-membered ring systems have one double bond, thefive-or six-membered ring systems have one or two double bonds, theseven- or eight-membered ring systems have one, two, or three doublebonds, and the nine- or ten-membered rings have one, two, three, or fourdouble bonds. Representative examples of monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, and cyclooctenyl. The monocycliccycloalkenyl ring may contain one or two alkylene bridges, eachconsisting of one, two, or three carbon atoms, each linking twonon-adjacent carbon atoms of the ring system. Representative examples ofthe bridged cycloalkenyl groups include, bur are not limited to,bicyclo[2.2.1]hept-2-enc. 4,5,6,7-tetrahydro-3aH-indene,octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic andbridged cycloalkenyl can be attached to the parent molecular moietythrough any substitutable atom contained within the ring systems.

The term “cycloalkyne,” or “cycloalkynyl” or “cycloalkynylene,” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkynyl has eight or more carbon atoms, zeroheteroatoms, and one or more triple bonds. The monocyclic cycloalkynylring may contain one or two alkylene bridges, each consisting of one,two, or three carbon atoms, each linking two non-adjacent carbon atomsof the ring system. The monocyclic and bridged cycloalkynyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “heteroarene,” or “heteroaryl,” or “heteroarylene, ” as usedherein, means a five-membered or six-membered aromatic ring having atleast one carbon atom and one or more than one independently selectednitrogen, oxygen or sulfur atom. The heteroarenes of this invention areconnected through any adjacent atoms in the ring, provided that propervalences are maintained. Representative examples of heteroaryl include,but are not limited to, furanyl (including, but not limited thereto,furan-2-yl), imidazolyl (including, but not limited thereto,1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl,pyridinyl (e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,1,3-thiazolyl, thienyl (including, but not limited thereto, thien-2-yl,thien-3-yl), triazolyl, and triazinyl.

The term “heterocycloalkane,” or “heterocycloalkyl,” or“heterocycloalkylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected front the group consistingof O, N, and S and zero double bonds. The monocyclic and bridgedheterocycloalkane are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkanegroups include, but are not limited to, 8-azabicyclo[3.2.1]octane,3-azabicyclo[3.2.2]nonane, morpholinyl, tetrahydropyranyl, pyrrolidinyl,piperidinyl, dioxolanyl, tetrahydrofuranyl, thiomorpholinyl,1,4-dioxanyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxetanyl,piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridinyl,diazepanyl, dithiolanyl, dithianyl, isoxazolidinyl, isothiazolidnyl,oxadiazolidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothienyl,thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithianyl, andtrithianyl.

The term “heterocycloalkene,” or “heterocycloalkenyl,” or“heterocycloalkenylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and one or more double bonds. The monocyclic and bridgedheterocycloalkene are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteratoms in theheterocyclic rings may optionally be oxidized and the nitrogen atom mayoptionally be quarternized. Representative examples of heterocycloalkenegroups include, but are not limited to, 1,4,5,6-tetrahydropyridazinyl,1,2,3,6-tetrahydropyridinyl, dihydropyranyl, imidazolinyl,isothiazolinyl, oxadiazolinyl, isoxazolinyl, oxazolinyl, pyranyl,pyrazolinyl, pyrrolinyl, thiadiazolinyl, thiazolinyl, and thiopyranyl.

The term “phenylene,” as used herein, means a divalent radical formed byremoval of a hydrogen atom from phenyl.

The term “spiroalkyl,” as used herein, means alkylene, both ends ofwhich are attached to the same carbon atom and is exemplified byC₂-spiroalkyl, C₃spiroalkyl, C₄-spiroalkyl, C₅-spiroalkyl,C₆-spiroalkyl, C₇-spiroalkyl, C₈-spiroalkyl, C₁₀-spiroalkyl and thelike.

The term “spiroheteroalkyl,” as used herein, means spiroalkyl having oneor two CH₂ moieties replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N.

The term “spiroheteroalkenyl,” as used herein, means spiroalkenyl havingone or two CH₂ moieties replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N and also means spiroalkenyl having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties replacedwith N.

The term, “spirocyclo” as used herein, means two substituents on thesame carbon atom, that, together with the carbon atom to which they areattached, form a cycloalkane, heterocycloalkane, cycloalkene, orheterocycloalkene ring.

The term “C₂-C₅-spiroalkyl,” as used herein, means C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl, and C₅-spiroalkyl.

The term “C₂-spiroalkyl,” as used herein, means eth-1,2-ylene, both endsof which replace hydrogen atoms of the same Ch₂ moiety.

The term “C₃-spiroalkyl” as used herein, means prop-1,3-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The terns “C₄-spiroalkyl” as used herein, means but-1,4-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkyl,” as used herein, means pent-1,5-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₆-spiroalkyl” as used herein, means hex-1,6-ylene, both endsof which replace hydrogen atoms of the same CH₃ moiety.

The terms “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benxzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidiene,3,3-dimethyl-5-oxycyclo-hexylidiene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acctylmethyl,benzoylmethyl, para-nitrobenzylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl,2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, propionyloxymethyl,phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl,2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl,triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, diphenylmethylsilyl, andtert-butylmethoxyphenyklsilyl.

The term “OH or SH protecting group.” as used hereto, meansbenzyloxycarbonyl, 4-nitrobenzyloxyocarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenyloxycarbonyl, 3,4-dimethoxybenzyoxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxyocarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilymethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyoxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl (phenylmethyl), para-methoxybenxyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and ter-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.Furthermore, the invention contemplates the various isomers and mixturesthereof resulting from the disposal of substituents around an adamantanering system. Two substituents around a single ring within an adamantanering system are designated as being of Z or E relative configuration.For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J, IeNoble J. Org. Chem. 1998, 63, 2758-2 760 and E. L. Elicl, and S. H.Wilen. (1994) Stereochemistry of Organic Compounds, New York, N.Y.:Joint Wiley & Sons. Inc.

Compounds of this invention contain asymmetrically substituted carbonatoms in the R or S configuration, in which the terms “R” and “S” are asdefined by the IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chens, (1976) 45, 13-10. Compounds havingasymmetrically substituted carbon-atoms with equal amounts of R and Sconfigurations are racemic at those carbon atoms. Atoms with an excessof one configuration over the other are assigned the configurationpresent in the higher amount, preferably an excess of about 85%-90%,more preferably an excess of about 95%-99%, and still more preferably anexcess greater than about 99%. Accordingly, this invention includes;racemic mixtures, relative and absolute stercoisomers, and mixtures ofrelative and absolute stercoisomers.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties mayhave attached thereto prodrug-forming moieties. The prodrug-formingmoieties are removed by metabolic processes and release the compoundshaving the freed hydroxyl, amino or carboxylic acid in vivo. Prodrugsare useful for adjusting such pharmacokinetic properties of thecompounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵O, ¹²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds that containother isotopes of these and/or other atoms are within the scope of thisinvention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J el al., J Med Chem. 39(3). 673(1996); Mallesham, B et al., Org Lett. 5 (7). 963 (2003): PCTpublications WO 1997010223, WO2005099353, WO 1995007271, WO2006008754:U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531685; 7,528,131; 7,521,421;7,514,068; 7,511,013: and U.S. Patent Application Publication Nos.20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-2 inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp., 2-36, Academic press,London. 1985; Kato et al., J. Labelled Comp. Radiopharmacent,36(10):927-932 (1995); Kushner et al. Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radio active isotope containing drugs, such asdeutcrated drugs called “heavy drugs,” can be used for the treatment ofdiseases and conditions related to Bcl-2 activity. Increasing the amountof an isotope present in a compound above its natural abundance iscalled enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96. to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks inmammals, including rodents and dogs, with minimal observed adverseeffects (Czajka D M and Finkel A J, Ann. N. Y. Acad. Sci. 1960 84:770:Thomson J F. Ann. New York Acad. Sci 1960 84:736; Czakja D M et al. Am.J. Physiol. 1961 201:357). Acute replacement of as high as 15%-23% inhuman fluids with deuterium was found not to cause toxicity (BlagojevicN et al. in “Dosimetry & Treatment Planning for Neutron CaptureTherapy”, Zamenhof R, Solares G. and Harling O Eds. 1994. AdvancedMedical Publishing, Madison Wis. pp. 125-134: Diabetes Metab. 23:251(1997)).

Stable Isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope as a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmeokinetic profile or efficacy relative to the non-isotopiccompound.

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, which are useful as selectiveinhibitors of one or more than one anti-apoptotic protein family member,the compounds having Formula (I), (II), or (III).

wherein

A¹ is N or C(A²):

A² is H, R¹, OR¹, SR¹, S(O)R¹, C(O)OR¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NCH(O)OR¹, NR¹C(O)OR¹,NCH(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹. NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹. C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂(CH₁)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂ N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A);

D¹ is H, R¹, OR¹, SR¹, SC(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹,NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO_(X)R¹, C(NH)NH₂, C(CH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹,NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F, Cl Br, I, CN, NO₂, N₃, OH, C(O)H,CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A);

E¹ is H, R¹ , OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹ , OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₃N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂(CH₃RN(CH₃)N(CH₃)R¹. F, Cl, B, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃),CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B) , is substituted orfurther substituted with S(O)₂(OH), C(O)OR⁵⁰OP(O)(OH)(OH),C(O)R⁵⁰OP(O)(OH)(OH), C(O)NH(R⁵⁰)NH₂, C(O)R⁵⁰C(O)NR⁵⁰, OR⁵⁰P(O)(OH)(OH), OP(O)(OH)(OH), or OC(O)CH₂OP(O)(OH)(OH):

R¹ and R^(1B) are each independently R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with benzene, heteroarene orR^(2A):R^(2A) is cycloalkane or heterocycloalkane:

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A):R^(3A) is cycloalkane or heterocycloalkane:

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene orR^(4A):R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three independently selected R⁶, NC(R^(6A))(R^(6B)),R², OR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷,NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂,NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₂CF₂CF₃, F, Cl, Br or I substituents:

R⁶ is C₂-C₄-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, , NH₂, NH(CH₃) or N(CH₁)₂;

R^(6A) and R⁶ are independently selected alkyl or, together with the Nto which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(10A), R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with benzene,heteroarene or R^(14A):R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(19A):R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene:

R²⁰ is C₃-C₁₀cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene:

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents.

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with benzene, heteroareneor R^(24A):R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(25A):R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene:

R³⁰ is cycloalkyl or cycloalkenyl each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₂, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene:

wherein R³⁰ is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR¹⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²R³⁷;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₄-spiroalkyl;

R³² is R³¹, C(O)R⁵³ or C(O)OR⁵³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with benzene, heteroarene, orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹:

R³⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(35A); R^(35A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene:

R³⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₁-C₈-cycloalkyl or C₄-C₈cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(40A); R^(40 A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane,. cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇- cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R^(b 45) is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R47 is phenyl which is unfused or fused with benzene, heteroarene orR^(43A); R^(43A)is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A) ; R^(48A) is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R² , R^(2A), R³, R^(3A), R⁴, R^(4A),R⁶, R^(6C), R⁸, R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A), R¹³, R^(13A), R¹⁴,R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A), R²⁰, R^(20A), R²³,R^(23A), R²⁴, R^(24A), R²⁴, R^(24A), R²⁵, R^(25A), R³⁰, RR^(30A), R³¹and R^(31A) taken together, R³⁴, R^(34A), R^(36A), R³⁸, R^(38A), R³⁹,R^(39A), R⁴⁰, R^(40A), R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴, R^(44A), R⁴⁷,R^(47A), R⁴⁸, R^(48A), R⁴⁹, and R^(49A) are independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five independently selected R⁵⁰, OR⁵⁰, SR⁵⁰,S(O)R⁵⁰, SO₂R⁵⁴, S(O)R⁵⁸, CO(O)R⁵⁸, OC(O)R³⁰, OC(O)OR³⁰, NH₂, NHR⁵⁰,N(R⁴⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰,C(O)NHSO₂R⁵⁰, C(O)NR⁵⁴SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃,C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R)R⁵⁰)₂, OH, (O), CN, N₁, NO₂,CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br OR I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(41B); R^(51B) is cycloalkene, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆- cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNHOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, and alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆ cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N.

In one embodiment of Formula (I), (II), or (III);

A¹ is C(A²):

A² is H:

B¹ s OR¹, or NHR¹:

D¹ is H:

E¹ is H:

Y¹ is NO₂;

G¹ is R^(1B), OR^(1B), NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B)is substituted or furthersubstituted with OP(O)(OH)(OH);

R¹ and R^(1B) are each independently R⁵:

R⁵ is alkyl, which is independently further unsubstituted, orsubstituted with R⁷:

R⁷ is R¹⁰:

R¹⁰ is C₃-C₁₀-cycloalkyl, each having one or two CH₂ moieties unreplacedor replaced with independently selected O:

R⁵⁰ is cycloalkyl or cycloalkenyl, each having one or two CH moietiesunreplaced or replaced with N:

wherein R³⁶ is substituted with CH₂R³⁷;

R³⁷ is R⁴⁰, each of which is substituted with R⁴¹;

R⁴⁰ is C₄-C₈-cycloalkenyl;

R⁴¹ is R⁴²;

R⁴² is phenyl:

wherein the moieties represented by R¹⁰, R⁴⁰, and R⁴² are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected R⁵⁰,OR⁵⁰, F, Cl, Br or I substituents;

R⁵⁰ is R⁵¹; and

R⁵⁵ is alkyl.

In another embodiment of Formula (I), (II), or (III): A¹ is C(A²); andA² is H. In another embodiment of Formula (I), (II), or (III): A¹ isC(A²); A² is H; and B¹ is OR¹, or NHR¹. In another embodiment of Formula(I), (II), or (III); A¹ is C(A²): A² is H; B¹ is OR¹, or NHR¹; and D¹ isH. In another embodiment of Formula (I), (II), or (III); A¹ is C(A²): A²is H; B¹ is OR¹, or NHR¹; D¹ is H; and E¹ is H. In another embodiment ofFormula (I), (II), or (III); A¹ is C(A²); A² is H; B¹ is OR¹, or NHR¹;is D¹ is H; E¹ is H; and Y¹ is NO₂.

In one embodiment of Formula (I), (II), or (III); G¹ is R^(1B), OR^(1B),or NHR^(1B). In another embodiment of Formula (I), (II), or (III): A¹ isC(A²); A² is H; B¹ is OR¹, or NHR¹: D¹ is H: E¹ is H; Y¹ is NO₂; and G¹is R^(1B), OR^(1B), or NHR^(1B).

In one embodiment of Formula (I), (II), or (III); G¹ is R^(1B), OR^(1B),or NHR^(1B); wherein the R^(1B), or a substituent on R^(1B), issubstituted or further substituted with OP(O)(OH)(OH). In anotherembodiment of Formula (I), (II), or (III); A¹ is C(A²): A² is H; B¹ isOR¹ or NHR¹; D¹ is H; E¹ is H; Y¹ is NO₂; and G¹ is R^(1B), OR^(1B), orNHR^(1B), wherein the R^(1B), or a substituent on R^(1B), is substitutedor further substituted with OP(O)(OH)(OH).

Still another embodiment pertains to compounds having Formula (I), (II)or (III) which are

(5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(13-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate;

{5-}5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[{(4-{[(trans-4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7yl}methyldihydrogen phosphate:

(5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate:

3-[(4-{[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-dimethylpropyldihydrogen phosphate;

trans-4-[(4-|[4-(4-{[2-4-chorophenyl-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2.3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2 -nitrophenoxyl)methyl]cyclohexyl dihydrogenphosphate; and therapeutically acceptable salts, and metabolitesthereof.

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, which are useful as selectiveinhibitors of one or more than one anti-apoptotic protein family member,the compounds having Formula (I)

wherein

A¹ is N or C(A²):

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R)¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR₁SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)₃NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹ ₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂ N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(LO)NH₂ or C(O)OR¹;

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, NHC(O)NHR³, NHC(O)N(R¹)₂, NR¹C(O)NHR¹NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₁(R¹, N(CH₃)SO₂N(CH₃)R¹, F,Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(A; and)

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹³, C(O)R¹⁷, C(O)OR¹⁷⁸, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR₁₇, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with S(O)₂(OH), C(O)OR⁵⁰OP(O)(OH)(OH),C(O)R⁵⁰OP(O)(OH)(OH), C(O)NH(R⁵⁰)NH₂, C(O)R⁵⁰C(O)NR⁵⁰; OR⁵⁰P(O)(OH)(OH),OP(O)(OH)(OH), or OC(O)CH₂OP(O)(OH)(OH);

R¹ and R^(1B) are each independently R², R³, R⁴ R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R₄ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloakenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁶ is alkyl, alkenyl or alkynyl, each of which is independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three independently selected R⁶, NC(R^(6A))(R^(6B)),R¹, OR⁷, SR⁷, S(O)R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR¹,NHC(OR)R¹, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂,NHC(O)NHR¹, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₁NHC(O)CH(CH₁)NHR¹, OH, (O), C(O)OH, (O), N₁, CN, NH₂, CF₁,CF₂CF₁F, Cl, Br or I substituents;

R⁶ is C₁-C₆-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₁, CF₂CF₃, F, CL, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C):

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH; moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₁-₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N, and each of which is unfused or fusedwith benzene, heteroarene or R^(10A); R^(10A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NHR¹², C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents:

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹¹ is heteroaryl, each of which is unfused or fused with benzene,heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀cycloalkyl or C₆-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is heteroarene which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₁-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₁, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein R³⁰ is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R)³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷ , SR³⁷, S(O)R³⁷, SO₂R³⁷L , NHR³⁷ orN(R³²)R³⁷;

R³¹ and R^(31A) are independently F, CL, Br or alkyl or are takentogether and are C₂-C₄-spiroalkyl;

R³² is R³³, C(O)R³³, or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with benzene, heteroarene, orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, CL, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₁-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₁, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocyloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₁-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR46,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or Il substituents;

R⁴⁶ is R⁴⁷, R⁴⁸, R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene:

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl each having one or two CH₂moieties unreplaced or replaced with independently selected O, (O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene:

wherein the moieties represented by R², R^(2A), R³, R^(3A), R⁴, R^(4A),R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A), R¹³, R^(13A), R¹⁴, R^(14A), R¹⁵,R^(15A), R¹⁶, R^(18A), R¹⁹, R^(19A), R²⁰, R^(20A), R²³, R^(23A), R²⁴,R^(24A), R²⁵, R^(25A), R³⁰, R^(30A), R³¹ and R^(31A) taken together,R³⁴, R^(34A), R³⁶, R^(36A), R³⁸, R^(38A), R³⁹, R^(39A), R⁴⁰, R^(40A),R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴, R^(44A), R⁴⁷, R^(47A), R⁴⁸, R^(48A),R⁴⁹, and R^(49A) are independently unsubstituted, further unsubstituted,substituted or further substituted with one or two or three or four orfive independently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R₅₀, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₂, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁴⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₂, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents:

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkene orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₁-C₄-cycloalkyl or C₄-C₆-cycloalkenyl, each having one two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents:

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶:

wherein the alkyl, alkenyl, and alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(o),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

In one embodiment of Formula (I):

A¹ is C(A²);

A² is H;

D¹ is H:

E¹ is H;

Y¹ is NO₂;

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with OP(O)(OH)(OH):

R¹ and R^(1B) are each independently R⁴;

R⁵ is alkyl, which is independently further unsubstituted, orsubstituted with R⁶;

R⁷ is R¹⁰;

R¹⁰ is C₃-C₁₀-cycloalkyl, each having one or two CH; moieties unreplacedor replaced with independently selected O;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH moietiesunreplaced or replaced with N;

wherein R³⁰ is substituted with CH₂R³⁷;

R³⁷ is R⁴⁰, each of which is substituted with R⁴¹;

R⁴⁰ is C₄-C₈-cycloalkenyl;

R⁴¹ is R⁴²:

R⁴² is phenyl;

wherein the moieties represented by R¹⁰, R⁴⁰, and R⁴² are independentlyunsubstituted, further unsubstituted substituted or further substitutedwith one or two or three or four or five independently selected R⁴⁰OR⁵⁰,F, Cl, Br or I substituents;

R⁵⁰ is R⁵⁴; and

R⁵⁴ is alkyl.

In another embodiment of Formula (I); A² is C(A²); and A² is H. Inanother embodiment of Formula (I); A¹ is C(A²): A² Is H; and D¹ is H. Inanother embodiment of Formula (I); A³ is C(A²): A² is H: D¹ is H; and E¹is H. In another embodiment of Formula (I); A¹ is C(A²); A² is H; D¹ isH: E¹ is H; and Y¹ is NO₂.

In one embodiment of Formula (I); G¹ is R^(1B), OR^(1B), or NHR^(1B). Inanother embodiment of Formula (I); A¹ is C(A²); A² is H; E¹ is H; Y¹ isNO₂; and G¹ is R^(1B), OR^(1B), or NHR^(1B).

In one embodiment of Formula (I): G¹ is R^(1B), OR^(1B), or NHR^(1B);wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with OP(O)(OH)(OH). In another embodiment of Formula(I); A¹ is C(A²); A² is H; D¹ is H; E¹ is H; Y¹ is NO₂ ; and G¹ isR^(1B), OR^(1B), or NHR^(1B); wherein the R^(1B), or a substituent onR^(1B), is substituted or further substituted with OP(O)(OH)(OH).

Still another embodiment pertains to compounds having Formula (I) whichare

3-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-dimethylpropyldihydrogen phosphate;

trans-4-[{(4-{(4-{2-|[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}2-nitrophenoxy)methyl]cyclohexyldihydrogen phosphate; and therapeutically acceptable salts, andmetabolites thereof.

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, which are useful as selectiveinhibitors of one or more than one anti-apoptotic protein family member,the compounds having Formula (II)

wherein

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NFC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)², NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂NHSO₂NHR¹, NHSO₂N(CH₃)R¹, N(CH₃)SO₂N(CH₂)R¹, F,Cl, Br, I, CN, NO₂, N₂, OH, C(O)H, CHNOH, CH(NOCH₂), CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(A);

B¹ is H, R², OR¹, SR¹, S(O)R¹, SO₁R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹(O)N(R²)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R³, F, Cl, Br, CN, NO₁, N₃, OH, C(O)H, CHNOH, CH(NOCH₃),CF₂, C(O)OH, C(O)NH₂ or C(O)OR^(A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂ , NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂ , NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl, Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹,NR¹C(O)OR¹, NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NH₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO₂R¹, NHSO₂NHR¹,NHSO₂N(R¹)₂, NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹,C(O)NHSO₂R¹, C(NH)NH₂, C(NH)NHR¹, C(NH)N(R¹)₂, NHSO₂NHR¹, NHSO₂N(CH₃)R¹,N(CH₃)SO₂N(CH₃)R¹, F, Cl Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH,CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷, OR¹⁷, O(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷,C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷), NHS(O)R¹⁷ or NHSO₂R¹⁷:

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B), substituted or furthersubstituted with S(O)₂(OH), C(O)OR^(5B)OP(O)(OH)(OH), C(O)R^(5B)OP(O)(OH)(OH), C(O)NH(R^(5B))NH₂, C(O)R^(5B)C(O)NR^(5B);OR^(5B)P(O)(OH)(OH), OP(O)(OH)(OH), OR OC(O)CH₂OP(O)(OH)(OH);

R¹ and R^(1B) are each independently R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is on fused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three independently selected R⁶, NC(R^(6A))(R^(6B)),R¹, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷), C(O)R⁷, C(O)NH₂, C(O)NHR⁷,NHC(O)R⁷, NHSO₂R¹, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂,NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₂, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₃-spiroalkyl each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, F, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH, S, S(O), SO₂ or NH:

R⁷ is R⁸, R⁹, R¹⁰ R¹¹;

R⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH; moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), S(O)₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents:

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with benzene,heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloakane,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(18A); R^(18 A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(19A) ; R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH; moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(20 A); R^(20 A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents:

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²³ is heteroarene which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH; moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein R³⁰ is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³, or C(O)OR₃₃;

R³³ is or R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with benzene, heteroarene. orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂ ⁴¹);

R³⁸ phenyl which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties, unreplaced or replaced with independently selected O, (O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkyl or C₄-C₇-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with benzene, heteroarene or R^(44A); R⁴⁴ is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstiuted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶), C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), O(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents:

R⁴⁶ IS r⁴⁷, r⁴⁸ OR r⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ societies unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₁, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N, and each of which is unfused or fusedwith benzene, heteroarene or R^(49A); R^(49A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R², R^(2A), R³, R^(3A), R⁴, R^(4A),R⁶, R^(6C), R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A), R¹³, R^(13A), R¹⁴,R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A), R²⁰, R^(20A), R²³,R^(23A), R³⁴³, R^(34A), R²⁵, R^(30A), R³¹ and R^(30A) taken together,R³⁴, R^(34A), R³⁶, R^(36A), R³⁸, R^(38A), R³⁹, R^(39A), R⁴⁰, R^(40A),R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴, R^(44A), R⁴⁷, R^(47A), R⁴⁸, R^(48A),R⁴⁹, and R^(49A) are independently unsubstituted, further unsubstituted,substituted or further substituted with one or two or three or four orfive independently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁴⁰, CO(O)R⁵⁰,OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR³⁵SO₂R³⁴, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₁, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or Isubstituents;

R⁵⁰ is R⁵³, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₄-cycloalkyl or C₄-C₆- cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁴,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NHR₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵³, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, and alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

In one embodiment of Formula (II):

A¹ is C(A²);

A² is H;

B¹ is OR¹, or NHR¹;

D¹ is H;

E¹ is H;

Y¹ is NO₂;

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with OP(O)(OH)(OH);

R¹ and R^(1B) are each independently R⁷;

R⁵ is alkyl, which is independently further unsubstituted, orsubstituted with R⁷;

R⁷ is R¹⁰;

R¹⁰ is C₃-C₁₀-cycloalkyl, each having one or two CH; moieties unreplacedor replaced with independently selected O;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH moietiesunreplaced or replaced with N:

wherein R³⁰ is substituted with CH₂R³⁷;

R³⁷ is R⁴⁶, each of which is substituted with R⁴¹;

R⁴⁰ is C₄-C₈-cycloalkenyl;

R⁴¹ is R⁴²;

R⁴² is phenyl;

wherein the moieties represented by R^(1B) , R^(1B), and R⁴² areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected OR⁵⁰, OR⁵⁰, F, Cl, Br or I substituents;

R⁵⁰ is R⁵⁴; and

R⁵⁴ is alkyl.

In another embodiment of Formula (II): A¹ is C(A²); and A² is H. Inanother embodiment of Formula (II); A¹ is C(A²); A² is H; and B¹ is OR¹,or NHR¹. In another embodiment of Formula (II): A¹ is C(A²); A² is H; B¹is OR¹, or NHR¹; and D¹ is H. In another embodiment of Formula (II): A¹is C)A²); A² is H; B¹ is OR¹, or NHR¹; D¹ is H; and E¹ is H. In anotherembodiment of Formula (II); A¹ is C(A²); A² is H; B¹ is OR¹, or NHR¹; D¹is H; E¹ is H; and Y¹ is NO₂.

In one embodiment of Formula (II): G¹ is R^(1B), OR^(1B), or NHR^(1B).In another embodiment of Formula (II); A¹ is C(A²); A² is H; B¹ is OR¹,or NHR¹; D¹ is H; E¹ is H; U¹ is NO₂; and G¹ is R^(1B), OR;^(1B), orNHR^(1B).

In one embodiment of Formula (II); G¹ is R^(1B), OR^(1B), or NHR^(1B);wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with OP(O)(OH)(OH). In another embodiment of Formula(II); A¹ is C(a²); A² is H; B¹ is OR¹ or NHR¹; D¹ is H; E¹ is H; Y¹ isNO₂; and G¹ is R^(1B), OR^(1B), or NHR^(1B), wherein the R^(1B), or asubstituent on R^(1B), is substituted or further substituted withOP(O)(OH)(OH).

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, which are useful as selectiveinhibitors of one or more than one anti-apoptotic protein family member,the compounds having Formula (III)

A¹ is N or C(A²);

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₁, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

G¹ is R^(1B), OR^(1B), or NHR^(1B),

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with S(O)₂(OH), C(O)OR⁵⁰OP(O)(OH)(OH),C(O)R⁵⁰OP(O)(OH)(OH), C(O)NH(R⁵⁰)NH₂, CO)R⁵⁰NR⁵⁰; OR⁵⁰P(O)(OH)(OH),OP(O))OH)(OH), or OC(O)CH₂op(O)(OH)(OH);

R¹ and R^(1B) are each independently R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₁-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with benzene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three independently selected R⁶, NC(R^(6A))(R^(6B)),R⁷, OR⁷, SR⁷, S(O)R⁷, SO₃R⁷, NHR⁷, N(R¹)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷,NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂,NHC(O)NHR⁷, NHC(O)CH(CH₁)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), n₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ C₂-C₆-spiroalkyl, each of which is unsubstituted or substituted withOH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₁)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1l-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with benzene. heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ C₃-C₁₀- cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, (O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which N unfused or fused with benzene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is infused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with benzene,heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁸ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₁C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(o),CNOH, CNOCH₃, S, S(O), SO₃ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²²OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)PH, N₁,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ R²⁵;

R²³ is phenyl which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) A is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-c₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein R³⁰ is substituted with F, CL, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³⁵)(R^(34A))(R¹⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₄-spiroalkyl;

R³³ is R³³, C(O)R³⁵, or C(O)OR³³;

R³⁵ is R³⁴ or R³⁴;

R³⁴ is phenyl which is unfused or fused with benzene, heteroarene, orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with benzene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, OR⁴¹, N HR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(40A); R^(40A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴³ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with benzene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₈-cycloalkyl or C₄-C₁-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴³ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁴⁶, OR⁴⁶,NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O) C(O)OH, N₃, CN,NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with benzene, heteroarene orR^(47A); R^(47A) A is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl;

R⁴⁹ is C₃-C₆-cycloalkyl or C₂-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₁, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R², R^(2A), R³, R^(3A), R⁵, R^(4A),R⁶, R⁶, R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A), R¹³, R^(13A), R¹⁴,R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A), R²⁰, R^(20A), R²³,R^(23A), R²⁴, R^(24A), R²⁵, R^(25A), R³⁰, R^(30A), R³¹ and R^(31A) takentogether, R³⁴, R^(34A), R³⁶, R^(36A), R³⁸, R^(38A), R³⁹, R^(39A), R⁴⁰,R^(40A), R⁴², R^(42A), R⁴³, R^(43A), R⁴⁴, R^(44A), R⁴⁷, R^(47A), R⁴⁸,R^(48A), R⁴⁹, and RR^(49A) are independently unsubstituted, furtherunsubstituted, substituted or further substituted with one or two orthree or four or five independently selected R⁵⁰, OR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰,C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂,C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰,C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃,CF₂CF₃, OCF₂, OCF₂CF₃, F, Cl, Br OR I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵³ is phenyl which is unfused or fused with benzene, heteroarene orR^(52B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene:

R⁵² is heteroaryl;

R⁵³ is C₃-C₄-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NH(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, BR or I substituents;

R⁵⁵ is alkyl, alkenyl or alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, and alkynyl are unsubstituted or substitutedwith OCH₃; and R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₃ or NH and one or two CHmoieties unreplaced or replaced with N.

In one embodiment of Formula (III);

A³ is C(A²);

A² is H;

B¹ is OR¹, or NHR¹;

D¹ is H;

E¹ is H;

Y¹ is NO₂;

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with OP(O)(OH)(OH);

R¹ and R^(1B) are each independently R⁴;

R⁵ is alkyl, which is independently further unsubstituted, orsubstituted with R⁷;

R⁷ is R¹⁰;

R¹⁰ is C₃-C₁₀-cycloalkyl, each having one or two CH₂ moieties unreplacedor replaced with independently selected O;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH moietiesunreplaced or replaced with N;

wherein R³⁰ is substituted with CH₂R³⁷;

R³⁷ is R⁴⁶, each of which is substituted with R⁴¹;

R⁴⁰ is C₄-C₈-cycloalkenyl;

R⁴¹ is R⁴²;

R⁴² is phenyl;

wherein the moieties represented by R⁴⁰, R⁴⁰, and R⁴² are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected OR⁵⁰,OR⁵⁰, F, Cl, Br or I substituents;

R⁵⁰ is R⁵⁴; and

R⁵⁴ is alkyl.

wherein the moieties represented by R⁴⁰, R⁴⁰, and R⁴² are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected R⁵⁰,OR⁵⁰, F, Cl, Br or I substituents:

R⁵⁰ is R⁵⁴; and

R⁵⁴ is alkyl,

In another embodiment of Formula (II): A¹ is C(A²); and A¹ is H. Inanother embodiment of Formula (III); A¹ is C(A²); A² ; A² is H: and B¹is OR¹, or NHR¹, in another embodiment of Formula (III); A¹ is C(A²); isH: B¹ is H: B¹ is OR¹, or NHR¹: and D¹ b is H. In another embodiment ofFormula (III); A¹ is C(A²): A² is H: B¹ is OR¹, or NHR¹; D¹ is H: and E¹is H. In another embodiment of Formula (III); A¹ is C(A²); A² is H; B¹is OR¹, or NHR¹: D¹ is H; is E¹ is H; and Y¹ is NO₂.

In one embodiment of Formula (III); G¹ is R^(1B), OR^(1B), or NHR^(1B).In another embodiment of Formula (III); A¹ is C(A²); A² is H; B¹ is OR¹,or NHR¹; D¹ is H; E¹ is H; Y¹ is NO₂; and G¹ is R^(1B), OR^(1B), orNHR^(1B).

In one embodiment of Formula (III); G¹ is R^(1B), OR^(1B), or NHR^(1B);wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with OP(O)(OH)(OH). In another embodiment of Formula(III); A¹ is C(A²); A² is H. B¹ is OR¹ or NHR¹; D¹ is H; E¹ is H; Y¹ isNO₂; and G¹ is R^(1B), OR^(1B), or NHR^(1B); wherein the R^(1B), or asubstituent on R^(1B), is substituted or further substituted withOP(O)(OH)(OH).

Still another embodiment pertains to compounds having Formula (III)which are(5-|5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(|3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy|-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate;

{5-[5-(4-|[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl|piperazin-1-yl)-2-|[4-{[(trans-4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl|methyl dihydrogen phosphate;

(5-|5-(4-|[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl|-piperazin-1-yl)-2-[(|4-|(4-flurorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl{sulfonyl)carbamoyl]phenoxy{-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate; and therapeutically acceptable salts, andmetabolites thereof.

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, which are useful as selectiveinhibitors of one or more than one anti-apoptotic protein family member,the compounds having Formula (Ia), (IIa), or (IIIa)

wherein

A¹ is N or C(A²):

A² is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A);

B¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A);

D¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A);

E¹ is H, R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)OR¹ , OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NR¹C(O)R¹, NHC(O)OR¹, NR¹C(O)OR¹,NHC(O)NH₂, NHC(O)NHR¹, NHC(O)N(R¹)₂, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NH₂,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NR¹SO²R¹, NHSO₂NHR¹, NHSO₂N(R¹)₂,NR¹SO₂NHR¹, NR¹SO₂N(R¹)₂, C(O)NHNOH, C(O)NHNOR¹, C(O)NHSO₂R¹, C(NH)NH₂,C(NH)NHR¹, C(NH)N(R¹)₂ NHSO₂NHR¹, NHSO₂N(CH₃(R¹, N(CH₃SO₂N(CH₃R¹, F, Cl,Br, I, CN, NO₂, N₃, OH, C(O)H, CHNOH, CH(NOCH₃), CF₃, C(O)OH, C(O)NH₂ orC(O)OR^(A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

G¹ is R^(1B), OR^(1B), or NHR^(1B),

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with S(O)₂(OH), C(O)OR⁵⁰OP(O)(OH)(OH),C(O)R⁵⁰OP(O)(OH)(OH), C(O)NH(R⁵⁰)NH₂, CO)R⁵⁰NR⁵⁰; OR⁵⁰P(O)(OH)(OH),OP(O))OH)(OH), or OC(O)CH₂op(O)(OH)(OH);

R¹ and R^(1B) are each independently R², R³, R⁴ or R⁵;

R^(1A is C) ₁C₆-alkyl, C₃-C₆-alkenyl or C₁C₆- alkynyl;

R² is phenyl which is unfused or fused with benzene, heteroarene, orR^(2A); R^(2A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR³¹; R^(3A) is cycloalkane, or heterocycloalkane;

R³ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with benzene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is independently orsubstituted further unsubstituted, substituted or further substitutedwith one or two or three independently selected R⁶, NC^(6A)(R^(6B)), R⁷,OR⁷, SR⁷, S(O)R⁷, NHR⁷, N(R⁷)₂, C(O)R¹, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷,NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, HC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₁)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₆-spiroalkyl, each of which is substituted or substituted withCH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br I, NH₂, NH(CH₃) or N(CH₃)₂;

R^(6A) AND R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₂ , S, S(O), SO₂ or NH;

R⁶ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(8A); R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene:

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, C(O), C(O)OH, N₃,CN, NH₂, CF₁, CF₂CF₃, F, Cl, Br or I substituents:

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with benzene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with benzene,heteroarene or R^(14A); R^(14 A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with benzene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with benzene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R¹⁰; R¹⁰ is cycloalkane, cycloalkene, heterocycloalkaneor heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², OH, (O), C(O)OH, (O), N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, BR or I substituents;

R⁵⁵ is alkyl, alkenyl or alkynyl, phenyl, heteroaryl or R⁵⁶;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with benzene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with benzene, heteroareneor R^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene.heterocycloalkane or heterocycloalkene;

wherein moieties represented by R², R^(2A), R³, R^(3A), R⁴, R^(4A), R⁶,R^(6C), R⁸, R^(8A), R⁹, R^(9A), R¹⁰, R^(10A), R¹³, R^(13A), R¹⁴,R^(14A), R¹⁵, R^(15A), R¹⁸, R^(18A), R¹⁹, R^(19A), R²⁰, R^(20A),R²³R^(23A), R²⁴, R^(24A), R²⁵, R^(25A), are independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five independently selected R⁵⁰, OR⁵⁰, SR⁵⁰,S(O)R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O))R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂,C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH, O(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰,C(O)NR⁵⁰SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H,C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂CF₂,CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is infused or fused with benzene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹ is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with benzene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵³ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₂, CF₃, CF₂CF₃, OCF₂CF₃, F,Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, and alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-c₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH; moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

In one embodiment of Formula (Ia), (IIa), or (IIIa);

A¹ is C(A²;

A² is H;

B¹ is OR¹or NHR¹;

D¹ is H;

E¹ is H;

Y¹ is NO₂;

G¹ is R^(1B), OR^(1B), or NHR^(1B);

wherein the R^(1B), or a substituent on R^(1B), is substituted orfurther substituted with OP(O)(OH)(OH);

R¹ and R^(1B) are each independently R⁵;

R⁶ is alkyl, which is independently further unsubstituted, orsubstituted with R⁷;

R⁷ is R¹⁰;

R¹⁰ is C₃-C₁₀-cycloalkyl, each having one or two CH₂ moieties unreplacedor replaced with independently selected O;

wherein the moieties represented by R⁵⁰ are independently unsubstituted,further unsubstituted, substituted or further substituted with one ortwo or three or four or five independently selected R⁵⁰, OR⁵⁰, F, Cl, Bror I substituents:

R⁵⁰ is R⁵⁴; and

R⁵¹ is alkyl,

R⁵⁴ is alkyl.

In another embodiment of Formula (Ia), (IIa), or (IIIa); A¹ is C(A²);and A² is H. In another embodiment of Formula (Ia), (IIa), or (IIIa); A¹is C(A²): A² is H; and B¹ is OR¹, or NHR¹. In another embodiment ofFormula (Ia), (IIa), or (IIIa); A¹ is A² is H; B¹ is OR¹, or NHR¹; andD¹ is H. In another embodiment of Formula (Ia), (IIa), or (IIIa); A¹ isC(A²): A² is H; B¹ is OR¹, or NHR¹; D¹ is H; and E¹ is H. In anotherembodiment of Formula (Ia), (IIa), or (IIIa); A¹ is C(A²); A² is H; B¹is OR¹, or NHR¹; D¹ is H: E¹ is H; and Y¹ is NO₂.

In one embodiment of Formula (Ia), (IIa), or (IIIa): G¹ is R^(1B),R^(OR) ^(1B), or NHR^(1B). In another embodiment of Formula (Ia), (IIa),or (IIIa); A¹ is C(A²); A² is H; B¹ is OR¹, or NHR¹; D¹ is H; E¹ is H;Y¹ is NO₂; and G¹ is R^(1B), OR^(1B), or NHR^(1B).

In one embodiment of Formula (Ia), (IIa), or (IIIa); G¹ is R¹, OR^(1B),or NHR^(1B); wherein the R^(1B), or a substituent on R^(1B), issubstituted or further substituted with OP(O)(OH)(OH). In anotherembodiment of Formula (Ia), (IIa), or (IIIa); A¹ is C(A²): A² is H; B¹is OR¹ or NHR¹; D¹ is H; E¹ is H; Y¹ is NO₂; and G¹ is R^(1B), OR^(1B),or NHR^(1B); wherein the R^(1B), or a substituent on is substituted orfurther substituted with OP(O)(OH)(OH).

Still another embodiment pertains to compounds having Formula (Ia),(IIa) or (IIIa) which are(5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl|piperazin-1-yl)-2-[(}3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy|-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate;

{5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl|methyl|piperazin-1-yl)-2-}[(4-}[(trans-4-methoxycyclohexyl)methyl]amino{-3-nitrophenyl)sulfonyl]carbamoyl{phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl|methyldihydrogen phosphate;

(5-{5-(4-{[2-(4-chlorophenyl)-4,-dimethylcyclohex-1-en-1-yl]methyl|piperazin-1yl)-2-[(}4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophneyl}sulfonyl)carbamoyl]phenoxy|-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate;

3-[4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-(dimethylpropyldihydrogen phosphate;

trans-4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2.3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}2-nitrophenoxy)methyl]cyclohexyldihydrogen phosphate; and therapeutically acceptable salts, andmetabolites thereof.

Pharmaceutical Compositions, Combination Therapies, Methods ofTreatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound having Formula (1) and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having Formula (1).

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having formula (1).

Still another embodiment pertains to compositions for treating diseasesduring which anti-apoptotic Bcl-2 proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (1).

Still another embodiment pertains to methods of treating disease in apatient during which anti-apoptotic Bcl-2 proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (1).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having Formula (1).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having Formula (1).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-2 proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (1) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-2 proteins, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (1) and a therapeuticallyeffective amount of one additional therapeutic agent or snore than oneadditional therapeutic agent.

Still another embodiment pertains to composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of thecompound having Formula (1) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myclogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound having Formula (1) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds having Formula (1), produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-2 proteins.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having Formula (1) may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-2 proteins.

Compounds having Formula (1) may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,malcate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, pierate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds and prodrugs thereof are contemplated as being embraced bythis invention. Basic addition salts of the compounds are those derivedfrom the reaction of the compounds with the hydroxide, carbonate orbicarbonate of cations such as lithium, sodium, potassium, calcium, andmagnesium.

The compounds having Formula (1) may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutancously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds having Formula (1) dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potency, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this inventionhaving Formula (1) used to make a composition to be administered dailyto a patient in a single dose or in divided doses is from about 0.03 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula (1) may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingFormula (1) to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl tumarate, sucrose, surfactants, tale, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (1) to be administered opthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (1) fit to be administered osmotically include,for example, chlorofluorohydrocarbon, ethanol, water and mixturesthereof. Excipients for preparation of compositions comprising acompound of this invention having Formula (1) to be administeredparenterally include, for example, 1,3-butanediol, castor oil, corn oil,cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleicacid, olive oil, peanut oil, Ringer's solution, safflower oil, sesameoil, soybean oil, U.S.P. or isotonic sodium chloride solution, water andmixtures thereof. Excipients for preparation of compositions comprisinga compound of this invention having Formula (1) to be administeredrectally or vaginally include, for example, cocoa butter, polyethyleneglycol, wax and mixtures thereof.

Compounds having Formula (1) are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitoties, antiproliferatives, antivirals, aurora kinase inhibitors,other apoptosis promoters (for example, Bcl-xL, Bel-w and Bfl-1)inhibitors, activators of death receptor pathway, Bcr-Abl kinaseinhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drugconjugates, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs,leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPs), intercalatingantibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,mammalian target of rapamycin inhibitors, micro RNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors, etinoidsdeltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs),topoisomerase inhibitors, ubiqutin ligase inhibitors, and the like, andin combination with one or more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′ and/or the3′-ends of a given strand. For example, siRNAs targeting Mel-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al.Cancer Research 2008, 68(9), 3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or move related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Muitispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostalliein, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan,rofosfantide and the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tic-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetresed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine, ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, ElCAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnyleytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemeitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptocurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, oefosfate, pelitrexol, pentoustatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737), N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roseovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARGφ (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her21lgG3, AS HER2 trifunctional bispecific antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-veMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators, of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5inhibitors such as AZD4877, ARRY-520:CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCl-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate)DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(ctodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplanin, lobaplatin, nedaplatin), PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-15658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Col.) and Chiron, (Emeryville, Calif.),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,cpirbuein, glarbuicin, ZA VEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeceamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-809155, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubiein),etoposide, exatecan, 10-hydroxycamptothein, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetaximab), HUMAX-CD4® (zanolimomab),IGF1 R-specific antibodies, lintuzumab, PANOREX® (edrecolomab),RENCAREX® (WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab,CD20 antibodies types I and II, GA 101, ofatumumab, ABT-806 (mAb-806),ErbB3 specific antibodies, BSG2 specific antibodies, DLL4 specificantibodies and C-met specific antibodies, and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrotelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer rcarbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include scocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vineristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NP1-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM -002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), (TLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin) NEUPOGEN® (filgrastim), OncoVAC-CL. OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin). obenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-lbritumomabriuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA°0 (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemeitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU 100940( 109881) patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having formula (1) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly 1:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidtonic acid), arglabin,L-asparaginase, atamestane (1methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN® ); P:prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TrandMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EPO906 (eptihilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histertelin, hydroxycarbamide, ibandronic acid, IGN-101,IL13-PE38, IL-13-PE38QQR (cintredekin besudotox). IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphosholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglueuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (and-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zurubicin and the like.

Data

Determination of the utility of compounds having Formula (1) as bindersto and inhibitor of anti-apoptotic Bcl-2 proteins was performed usingthe Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.PV4216).

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwisespecified. Peptide synthesis reagents including diisopropylethylamine(DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained fromApplied Biosystems, Inc. (ABI), Foster City, Calif. or AmericanBioanalytical, Natick, Mass., Preloaded 9-Fluorenylmethyloxycarbonyl(Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH,Fmoc-His(Trt)-OH, Fmoc-11e-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH,Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Sert(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH,Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec,San Jose, Calif. The peptide synthesis resin (Fmoc-Rink amide MBHAresin) and Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,Calif. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS)was obtained front Anaspec. Trifluoroacetic acid (TFA) was obtained fromOakwood Products, West Columbia, S.C. Thioanisole, phenol,triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) andisopropanol were obtained from Aldrich Chemical Co. Milwaukee, Wis.Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) wererecorded on an Applied Biosystems Voyager DE-PRO MS). Electrospraymass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp.,San Jose, Calif.) in both positive and negative ion mode.

General Procedure For Solid-Phase-Peptide Synthesis (SPPS)

Peptides were synthesized with, at most, 250 μmol preloaded Wangresin/vessel on an ABI 433A peptide synthesizer using 250 μmol scaleFastmoc™ coupling cycles. Preloaded cartridges containing 1 mmolstandard Fmoc-amino acids, except for the position of attachment of thefluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge,were used with conductivity feedback monitoring. N-terminal acetylationwas accomplished by using 1 mmol acetic acid in a cartridge understandard coupling conditions.

Removal of 4-Methyhtrityl (Mtt) from Lysine

The resin from the synthesizer was washed thrice with dichloromethaneand kept wet, 150 mL of 95:4:1dichloromethane:triisopropylsilane:trifluoroacetic acid was flowedthrough the resin bed over 30 minutes. The mixture turned deep yellowthen faded to pale yellow. 100 mL of N,N-dimethylformamide was flowedthrough the bed over 15 minutes. The resin was then washed thrice withN,N-dimethylformamide and filtered. Ninhydrin tests showed a strongsignal for primary amine.

Resin Labeling With 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1%DIEA/N,N-dimethylformamide and stirred or shaken at ambient temperatureovernight. When complete, the resin was drained, washed thrice withN,N-dimethylformamide, thrice with (1× DCM and 1× methanol) and dried toprovide art orange resin that was negative by ninhydrin test.

General Procedure for Cleavage and Deprotection Of Resin-Bound Peptide

Peptides were cleaved from the resin by shaking for 3 hours at ambienttemperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5%thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). Theresist was removed by filtration and rinsing twice with TFA. The TFA wasevaporated from the filtrates, and product was precipitated with ether(10 mL/0.1 g resin), recovered by centrifugation, washed twice withether (10 mL/0.1 g resin) and dried to give the crude peptide.

General Procedure For Purification Of Peptides

The crude peptides were purified on a Gilson preparative HPLC systemrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wisc.) ona radial compression column containing two 25×100 mm segments packedwith Delta-Pak™ C18 15 μm particles with 100 Å pore size and eluted withone of the gradient methods listed below. One to two milliliters oferude peptide solution (10 mg/mL in 90% DMSO/water) was purified perinjection. The peaks containing the products(s) from each run werepooled and lyophilized. All preparative runs were run at 20 mL/min witheluents as buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure For Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series systemwith a diode-array detector and a Hewlett-Packard 1046A fluorescencedetector running HPLC 3D ChemStation software version A.03.04(Hewlett-Packard, Palo Alto, Calif.) on a 4.6×250 mm YMC column packedwith ODS-AQ 5 μm particles with a 120 Å pore size and eluted with one ofthe gradient methods listed below after preequilibrating at the startingconditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water-andbuffer B: acetonitrile. The flow rate for all gradients was 1 mL/min

F-Bak: Peptide Probe Acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ IDNO:2INR-NH₂

Fmoc-Rink amide MBHA resin was extended using the general peptidesynthesis procedure to provide the protected resin-bound peptide (1.020g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved anddeprotected as described hereinabove to provide the crude product as anorange solid (0.37 g). This product was purified by RP-HPLC. Fractionsacross the main peak were tested by analytical RP-HPLC, and the purefractions were isolated and lyophilized, with the major peak providingthe title compound (0.0802 g) as a yellow solid; MALDI-MS m/z 2137.1[(M+H)′].

Alternative Synthesis of Peptide Probe F-Bak: Acctyl-(SEQ ID NO:1)GQVGRQLA11GDK(6-FAM)-(SEQ ID NO:2)INR-NH₂

The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHAresin (Novabiochem) on an Applied Biosystems 433A automated peptidesynthesizer running Fastmoc™ coupling cycles rising pre-loaded 1 mmolamino acid cartridges, except for the fluorescein(6-FAM)-labeled lysine,where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge.The N-terminal acetyl group was incorporated by putting 1 mmol aceticacid in a cartridge and coupling as described hereinabove. Selectiveremoval of the 4-methyltrityl group was accomplished with a solution of95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,followed by quenching with a flow of dimethylformamide. Single-isomer6-carboxyfluorescein-NHS was reacted with the lysine side-chain in 1%DIEA in N,N-dimethylformamide and confirmed complete by ninhydrintesting. The peptide was cleaved from the resin and side-chainsdeprotected by treating with 80:5:5:5:2.5:2.5TFA/water/phenol/thioanisole/triisopropylsilane:3.6-dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide wasrecovered by precipitation with diethyl ether. The crude peptide waspurified by reverse-phase high-performance liquid chromatography, andits purity and identity were confirmed by analytical reverse-phasehigh-performance liquid chromatography and matrix-assistedlaser-desorption mass-spectrometry (m/z=2137,1 ((M+H))).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay

Representative compounds were serially diluted in dimethyl sulfoxide(DMSO) starting at 50 μM (2× starting concentration; 10% DMSO) and 10 μLwere transferred into a 384-well plate. Then 10 μL of aprotein/probe/antibody mix was added in each well at finalconcentrations lifted in TABLE 1. The samples are then mixed on a shakerfor 1 minute and incubated for an additional 3 hours at roomtemperature. For each assay, the probe/antibody andprotein/probe/antibody were included on each assay plate as negative andpositive controls, respectively. Fluorescence was measured on theEnvision (Perkin Elmer) using a 340/35 nm excitation fiber and 520/525(F-Bak peptide) and 495/510 nm (Tb-labeled anti-Histidine antibody)emission filters. Inhibition constants (Ki) are shown in TABLE 2 belowand were determined using Wang's equation (Wang Z.-X. An ExactMathematical Expression For Describing Competitive Binding Of TwoDifferent Ligands To A Protein Molecule. FEBS Lett. 1995,360:111-4).

TABLE 1  Protien, Probe And Antibody Used For TR-FRET Assay Anti-Protien Probe body Protien Probe (nM) (nM) Antibody (nM) GST-Bel-2F-Bak  1 100 Tb-anti- 1 Peptide Probe GST Acetyl-(SEQ  ID NO: 1GQVGRQLAIIGDK (6-FAM) SEQ  ID NO: 2 INR-amide) 6-FAM =6-carboxyflouresecin; Tb = terbium; GST = glutathione S-transferase

The samples were then mixed on a shaker for 1 minute and incubated foran additional 3 hours at room temperature. For each assay, theprobe/antibody and protein/probe/antibody were included on each assayplate as negative and positive controls, respectively. Fluorescence wasmeasured on the Envision (Perkin Elmer) using a 340/35 nm excitationfilter and 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeledanti-Histidine antibody) emission filters.

Inhibition constants (K_(i)) for compounds according to the inventionare shown so TABLE 2 below. Where the K_(i) for a compound isrepresented as “>” (greater than) a certain numerical value, it isintended to mean that the binding affinity value is greater than thelimits of detection of the assay used. Where the K_(i) for a compound isrepresented as “<” (less than) a certain numerical value, it is intendedto mean that the binding affinity value is lower than the limit ofdetection of the assay used.

TABLE 2 TR-FRET Bcl-2 Binding Ki (μM) Example No. TR-FRET Binding: Bcl-2Ki (μM) 1 <0.000010 2 <0.000010 3 <0.000010 4 <0.000010 5 <0.000010

The inhibition constant (K_(i)) is the dissociation constant of anenzyme-inhibitor complex or a protein/small molecule complex, whereinthe small molecule is inhibiting binding of one protein to anotherprotein. So a large K_(i) value indicates a low binding affinity and asmall K_(i) value indicates a high binding affinity.

The data in TABLE 2 shows inhibition constants for the inhibition of aBak BH3 peptide probe to Bcl-2 protein and indicate that compoundsaccording to the; invention have high binding affinities foranti-apoptotic Bcl-2 protein. The compounds are therefore expected tohave utility in treatment of diseases during which anti-apoptotic Bcl-2protein is expressed,

RS4; 11 Cell Viability Assay

The acute lymphoblastic leukemia (ALL) cell line RS4:11 was used as theprimary human cell line to assess the cellular activity of Bcl-2selective agents in vitro and their efficacy in vivo. Previous studieshave shown by BH3 profiling, a mitochondrial assay that classifiesblocks in the intrinsic apoptotic pathway, that RS4:11 cells were highlydependant on BCL-2 for survival and sensitive to the Bcl-2 family memberinhibitor ABT-737 (Blood, 2008, Vol. 111, 2300-2309). The prevalence ofBcl-2 completed to the proapoptotic BH3 protein Bim in RS4:11 suggeststhat these cells are “primed” or more susceptible to cell death byantagonism of the antiapoptotic protein Bcl-2 for which they depend onfor survival.

RS4:11 cells were cultured in RPMI-1640 supplemented with 2 mML-glutamine, 10% FBS, 1 mM sodium pyruvate. 2 mM HEPES, 1%penicillin/streptomycin (Invitrogen), 4.5 g/L glucose and maintained at37 C. containing 5% CO₂. To test for the cellular activity of compoundsin vitro, cells were treated at 50,0000 cells per well in 96-wellmicrotiter plates in the presence of 10% human serum for 48 hours in ahumidified chamber with 5% CO₂. Cell cytotoxicity EC₅₀ values wereassessed tiding CellTiter Glo (Promega) according to the manufacturer'srecommendations. The EC₅₀ values were determined as a percentage ofviable cells following treatment compared to the untreated controlcells.

TABLE 3 RS4:11 EC₅₀ Values (μM) EXAMPLE # EC₅₀ 1 0.31 2 0.18 3 0.0414 >1 5 0.042

TABLE 3 shows the utility of compounds having Formula 1 to functionallyinhibit anti-apoptotic Bcl-2 protein in a cellular context. The acutelymphoblastic leukemia (ALL) cell line RS4:11 has been shown by BH3profiling, a mitochondrial assay that classifies blocks in the intrinsicapoptotic pathway, to be highly dependant on Bcl-2 for survival and issensitive to the Bcl-2 family member inhibitor ABT-737 (Blood, 2008.Vol. 111, 2300-2309). The ability of compounds to kill RS4:11 cells is adirect measure of the compounds ability to inhibit anti-apoptotic Bcl-2protein function. Compounds of Formula I are very effective in killingRS4; 11 cells its demonstrated by low EC₅₀ values.

The neutral form of compounds are generally and considerably morepermeable than the charged form (Chakrabarti, A. C.; Clark-Lewis. L:Harrigan, P. R.; Cullis, P. R. Biophysical Journal, 1992, 61, 228-234).Furthermore, the presence of a charged residue can result in apermeability rate of up to 10 times slower than that observed for thecorresponding neutral species (Ellens, H.: Eddy, E. P.; Lee, C.;Dougherty, P.; Lago, A.; Xiang, J.; Elliot, J. D.; Cheng, H; Ohlstein,E.: Smith. P. Advanced Drug Delivery Reviews. 1997, 23, 99-409).Compounds of this invention contain a phosphate group, which is expectedto be negatively charged at physiological pH, in addition to anacylsulfonamide moiety, which is also expected to be negatively chargedat physiological pH. It is therefore expected that compounds of theinvention, which contain multiple negative charges at physiological pH,would not be able to penetrate the cell membrane of RS4; 11 cells andinduce apoptosis, or programmed cell death. As demonstrated in Table 3,compounds of this invention are unexpectedly capable of penetrating thecell membrane and inducing programmed cell death.

Solubility Determination

Reagents used included 0.1 HCl, J T Baker Lot G08515; and 50 mMPhosphate pH 7.4, μ−0.155 w/NaCl, NB93214-089. Equipment/Instrumentsused included balance; Mettler Toledo, UMX2, LC805269; Rainin Pipette:1000 μL RF09683 μL. 200 μL RF20783; water bath: Vankel, LC 954896, setat 25° C. and 25 RPM. Thermometer: TB085688); and water bath: Vankel, LC127535, set at 37° C. and 25 RPM. Thermometer: TB096544).

Examples were tested in aqueous media at 25° C. or 37° C. Excess amountof the bulk drug was weighed out and mixed with an aliquot of targetmedia in a clear glass vial. The vial was sealed with cap and wrappedwith aluminum foil, then tumbled in a 25° C. or 37° C. water bath asappropriate. When equilibration was completed, the samples were removedfrom the water bath and the final pH's were measured. The suspensionswere filtered through 4 mm, 0.2 μm Millex-LG syringe filters(hydrophilic PTFE membrane, Millipore, Lot N9JN70696). Each filter wasused only for one sample and the first three droplets were discarded.The filtrate was assayed after appropriate dilution with the samesolvent as used for stock solution. Three replicates were prepared. Theconcentration of the sample was calculated against the calibration curvefor the compound.

TABLE 4 Aqueous Solubility at pH 7.4 Example Aqueous Solubility (pH 7.4,ug/mL 1 >1159 2 >4820 3 >10850 4 169 5 >6580 1M <1 2B <4 3E <1 6 <1 7 <1nd = not determined

The data in Table 4 shows the increased aqueous solubility of Examples1-5, which arc compounds of this invention, over the parent compoundsExamples 1M, 2B, 3E, 6, and 7.

The importance of solubility on immediate-release solid oral dosageforms can be found at U.S. Department of Health and Human Services, Foodand Drug Administration, Waiver of In Vivo Bioavailability andBioequivalence Studies for Immediate-Release Solid Oral Dosage FormsBased on a Biopharmaceuties Classification System, Food and DrugAdministration Center for Drug Evaluation and Research (CDER) [online],August 2000 [retrived May 19, 2010]. Retrieved from the Internet:>URL:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf<.

A report on the influence of solubility on the oral bioavailability ofdrugs can be found at WEI-QUIN TONG. Developability AssessmentSupporting Drug Candidate Selection, Integrated Drug Product DevelopmentProcess, University of Utah [online], July 17-19, 2006 [retrieved May14, 2010]. Retrieved from the Internet:>URL:

http://www.pharmacy.utah.edu/pharmaceutics/pdf/Developability.pdf<.

It is expected that, because compounds having Formula I bind to Bcl-2,they would also have utility as binders to anti-apoptotic proteinshaving close structural homology to Bcl-2, such as, for example,anti-apoptotic Bcl-X_(t), Bcl-w, Mcl-1 and Bfl-1/A1 proteins.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myclogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, spleen cancer, and the like is described in commonly-owned PCTUS 2004/36770, published as WO 2005/049593, and PCT US 2004/37911,published as WO 2005/024636.

Involvement of Bcl-2 proteins is immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.

Involvement of Bcl-2 proteins in arthritis is disclosed incommonly-owned United States Provisional Patent Application Ser. No.60/988,479.

Involvement of Bcl-2 proteins in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196.

Overexpression of Bcl-2 proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but are not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer,endostheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophoblastic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostatecancer (including hormone-insensitive (refractory) prostate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds having formula (1) would inhibitgrowth of cells expressing Bcl-2 proteins derived front a pediatriccancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, and thrombocytopenia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia areata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis, Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycaemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic cosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,common varied immunodeficiency (common variable hypogammaglobulinaemia),conjunctivitis, connective tissue disease associated interstitial lungdisease, contact dermatitis, Coombs positive haemolytic anaemia, corpulmonale, Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis,cryptogenic fibrosing alveolitis, culture negative sepsis, cysticfibrosis, cytokine therapy associated disorders, Crohn's disease,dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever,dermatitis, scleroderma, dermatologic conditions,dermatomyositis/polymyositis associated lung disease, diabetes, diabeticarteriosclerotic disease, diabetes mellitus, Diffuse Lewy body disease,dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupuserythematosus, disorders of the basal ganglia, disseminatedintravascular coagulation, Down's Syndrome in middle age, drug-inducedinterstitial lung disease, drug-induced hepatitis, drug-induced movementdisorders induced by drugs which block CNS dopamine, receptors, drugsensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy,enteropathic synovitis, epiglottitis, Epstein-Barr virus infection,etythromelalgia, extrapyramidal and cerebellar disorders, familialhematophagocytic lymphohistiocytosis, fetal thymus implant rejection,Friedreich's ataxia, functional peripheral arterial disorders, femaleinfertility, fibrosis, fibrotic lung disease, fungal sepsis, gasgangrene, gastric ulcer, giant cell arteritis, glomerular nephritis,glomerulonephritides, Goodpasture's syndrome, goitrous autoimmunehypothyroidism (Hashimoto's disease), gouty arthritis, graft refectionof any organ or tissue, graft versus host disease, gram negative sepsis,gram positive sepsis, granulomas due to intracellular organisms, group Bstreptococci (GBS) infection, Grave's disease, haemosiderosis associatedlung disease, hairy cell leukemia, hairy cell leukemia,Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, hearttransplant rejection, hemachromatosis, hematopoietic malignancies(leukemia and lymphoma), hemolytic anemia, hemolytic uremicsyndrome/thrombolytic thrombocytopenic purpura, hemorrhage,Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIVinfection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism,Huntington's chorea, hyperkinetic movement disorders, hypersensitivityreactions, hypersensitivity pneumonitis, hyperthyroidism, hypokineticmovement disorders, hypothalamic-pituitary-adrenal axis evaluation,idiopathic Addison's disease, idiopathic leucopaenia, idiopathicpulmonary fibrosis, idiopathic thrombocytopaenia, idiosyncratic liverdisease, infantile spinal muscular atrophy, infectious diseases,inflammation of the aorta, inflammatory bowel disease, insulin dependentdiabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/opticneuritis, ischemia-reperfusion injury, ischemic stroke, juvenilepernicious anaemia, juvenile rheumatoid arthritis, juvenile spinalmuscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidneytransplant rejection, legionella, leishmuniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidema, liver transplantrejection, Lyme disease, lymphederma, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemyeloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, mycobacteriumavium intracellulare, mycobacterium tuberculosis, myclodyplastiosyndrome, myocardial infarction, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epidydimitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, parathyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaccus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive sopranucleo Palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, radiation therapy, Raynaud'sphenomenon and disease, Raynoud's disease, Refsum's disease, regularnarrow QRS tachycardia, Reiter's disease, renal disease NOS,renovascular hypertension, reperfusion injury, restrictivecardiomyopathy, rheumatoid arthritis associated interstitial lungdisease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsissyndrome, septic shock, seronegative arthropathies, shock, sickle cellanemia, Sjögren's disease associated lung disease, Sjögren's syndrome,skin allograft rejection, skin changes syndrome, small bowel transplantrejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinalataxia, spinocerebellar degenerations, spondyloarthropathy, sporadic,polyglandular deficiency type I, sporadic polyglandular deficiency typeII, Still's disease, streptococcal myositis, stroke, structural lesionsof the cerebellum, Subacute sclerosing panencephalitis, sympatheticophthalmia. Syncope, syphilis of the cardiovascular system, systemicanaphylaxis, systemic inflammatory response syndrome, systemic onsetjuvenile rheumatoid arthritis, systemic lupus erythematosus, systemiclupus eryshcmatosus-associated lung disease, systemic sclerosis,systemic sclerosis-associated interstitial lung disease, T-cell or FABALL, Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th1 Typemediated diseases, thromboangitis obliterans, thrombocytopenia,thyroiditis, toxicity, toxic shock syndrome, transplants,trauma/hemmorhage, type-2 autoimmune hepatitis (anti-LKM antibodyhepatitis), type B insulin resistance with acanthosis nigricans, typeIII hypersensitivity reactions, type IV hypersensitivity, ulcerativecolitic arthropathy, ulcerative colitis, unstable angina, uremia,urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins,vasculitis, vasculitic diffuse lung disease, venous diseases, venousthrombosis, ventricular fibrillation, vitiligo acute liver disease,viral and fungal infections, vital encephalitis/aseptic meningitis,vital-associated hemaphagocytic syndrome, Wegener's granulomatosis,Wernicke-Korsakoff syndrome. Wilson's disease, xenograft rejection ofany organ or tissue, yersinia and salmonella-associated arthropathy andthe like.

Schemes and Experimental

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine: AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄; 9-BBN means9-borabicyclo(3,3,1)nonane: Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine, 1,4-phthalazinediyl diethyl ether: DBU means1,8-diazubicyclo[5.4.0]undec-7-ene: DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimmethylformantide; dmpe means1,2-bis(dimethylphosphinoethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane: FDAC·HCl mean1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: Fmoc meansfluorenylmethoxycarbonyl: HATU meansO-(7-azabenzotriazol-1-yl)-N,N′N′,N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid: THF means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine: PPh₃ means triphenylphosphine.

The following schemes are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. Compounds of this invention may bemade by synthetic chemical processes, examples of which are shownherein. It is means to be understood that the order of the steps in theprocesses may be varied, that reagents, solvents and reaction conditionsmay be substituted for those specifically mentioned, and that vulnerablemoieties may be protected and deprotected, as necessary.

Compounds of Formula (4) can be prepared as shown in SCHEME 1, and canbe used as described in SCHEME 7 to prepare compounds of Formula (1),which are representative of the compounds of the present invention.Compounds of Formula (1) wherein R is alkyl, can be converted tocompounds of Formula (2) using R³⁷CH² MgX¹, wherein X¹ is a halide, in asolvent such as but not limited to ether or tetrahydrofuran. Compoundsof Formula (3) can be prepared from compounds of Formula (2) using astrong base such as NaH and R⁵⁰X², wherein X² is a halide and R⁵⁰ is asdescribed herein. Compounds of Formula (3), when treated with aqueousNaOH or LiOH, will provide compounds of Formula (4).

As shown in SCHEME 2, compounds of Formula (5) can be reacted withcompounds of Formula (6) and a reducing agent to provide compounds ofFormula (7). Examples of reducing agents include sodium borohydride,sodium cyanoborohydride, sodium triacetoxyborohydride, polymer supportedcyanoborohydride, and the like. The reaction is typically performed in asolvent such as but not limited to methanol, tetrahydrofuran, anddichloromethane or mixtures thereof. Compounds of Formula (8) can beprepared from compounds of Formula (7) as described in SCHEME 1, and canbe used as described in SCHEME 7 to prepare compounds of Formula (1).

Compounds of Formula (9), when reacted with a compound a Formula (10)wherein X is a halide or triflate, and a base will provide a compound ofFormula (11). Bases useful in the reaction include triethylamine,diisopropylethylamine and the like. Compounds of Formula (13), whereinR⁴¹ is as described herein for substituents on R³⁷, can be prepared fromcompounds of Formula (11) and compounds of Formula (12) using Suzukicoupling conditions known to those skilled in the art and readilyavailable in the literature. Compounds of Formula (14) can be preparedfrom compounds of Formula (13) as described in SCHEME 1, and can be usedas described in SCHEME 7 to prepare compounds of Formula (1).

As shown in SCHEME 4, compounds of Formula (17) can be prepared fromcompounds of Formula (15) and compounds of Formula (16), wherein R isalkyl and R⁴¹ is as described herein, using Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature. Compounds of Formula (17) can be reduced to compounds ofFormula (18) using a reducing agent such as LiAlH₄ in a solvent such asbut not limited to diethyl ether or THF. Compounds of Formula (19) canbe prepared from compounds of Formula (18) using Dess-Martin periodinaneor Swern oxidation conditions known to those skilled in the art andreadily available in the literature. Compounds of Formula (19) can bereacted with a compound of Formula (5) and a reducing agent to providecompounds of Formula (20). Examples of reducing agents include sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,polymer supported cyanoborohydride, and the like. The reaction istypically performed in a solvent such as but not limited to methanol,tetrahydrofuran, 1,2-dichloroethane, and dichloromethane or mixturesthereof. Compounds of Formula (21) can be prepared from compounds ofFormula (20)as described in SCHEME 1, and can be used as described inSCHEME 7 to prepare compounds of Formula (1).

As shown in SCHEME 5, compounds of Formula (22), wherein R is alkyl, maybe converted to compounds of Formula (23) by reacting the former,wherein X¹ is Cl, Br, I, or CF₂SO₃, and compounds of FormulaR^(50A)—-OH, wherein R^(50A) is 1H-pyrrolo[2,3-b]pyridinyl, and acatalyst, with or without a first base. Examples of catalysts includecopper(1) trifluoromethanesulfonate toluene complex, PdCl₂, Pd(OAc)₂,and Pd₂dba)₃. Examples of first bases include triethylamine,N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, and mixtures thereof.

Compounds of Formula (22) may also be converted to compounds of Formula(23) by reacting the former, when X¹ is Cl, F, or NO₂, and compounds ofFormula R^(50A)—OH with a first base. Examples of first bases includemethylamine, N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, andmixtures thereof.

Compounds of Formula (18) can be reacted with mesyl chloride and a basesuch as but not limited to triethylamine, followed byN-t-butoxycarbonylpiperazine, to provide compounds of Formula (24).Compounds of Formula (25) can be prepared by reacting compounds ofFormula (24) with triethylsilane and trifluoroacetic acid. Compounds ofFormula (25) can be reacted with compounds of Formula (26) and HK₂PO₄ toprovide compounds of Formula (27) in a solvent such as but not limitedto dimethylsulfoxide, Compounds of Formula (28) can be prepared fromcompounds of Formula (27) as described in SCHEME 1, and can be used asdescribed in SCHEME 7 to prepare compounds of Formula (1).

As shown in SCHEME 7, compounds of Formula (32), which can be preparedas described herein, may be converted to compounds of Formula (33) byreacting the former with ammonia. Compounds of Formula (33) may beconverted to compounds of Formula (1) by reacting the former andcompounds of Formula (4), (8), (14), (21), (23), (28), or (38) and acoupling agent, with or without a first base. Examples of couplingagents include 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride, 1,1′-carbonyldiimidazole, andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.Examples of first bases include triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

Compounds of Formula (33), prepared as described in SCHEME 7, can alsobe converted to compounds of Formula (1) by reacting the former andcompounds of Formula (34) and a first base. Examples of first basesinclude but are not limited to sodium hydride, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

As shown in SCHEME 9, compounds of Formula (35), wherein L is O, can bereacted with compounds of Formula (36), to provide compounds of Formula(37). The reaction is typically performed at elevated temperatures in asolvent such as but not limited to dimethylsulfoxide, and may requirethe use of a base such as but not limited to potassium phosphate,potassium carbonate, and the like. Compounds of Formula (38) can beprepared from compounds of Formula (37) as described in SCHEME 1, andcan be used as described in SCHEME 7 to prepare compounds of Formula(1).

Compounds of Formula (39), wherein Y is as described herein forsubstituents on R³⁷, can be prepaid from compounds of Formula (39A)wherein X is a halide or triflate, and Y—B(OH)₂ using Suzuki couplingconditions known so those skilled in the art and readily available inthe literature. Compounds of Formula (39) can be reacted with tert-butylpiperazine-1 -carboxylate and a reducing agent such as sodiumtriacetoxyborohydride to provide compounds of Formula (40). The reactionis typically performed in a solvent such as but not limited to methylenechloride. Compounds of Formula (41) can be prepared from compounds ofFormula (40) by reacting the latter with R⁵⁰X, wherein X is a halide,and NaH in a solvent such as N,N-dimethylformamide, and then theresulting material can be treated with triethylsilane andtrifluoroacetic acid in dichloromethane. Compounds of Formula (41) canbe used as described in Scheme 9 wherein CH₂R³⁷ is as shown in Formula(41).

As shown in SCHEME 11, substituted piperazin-2-ones wherein R⁵⁰ isalkyl, can be reacted with compounds of Formula (6a) and a reducingagent such as sodium triacetoxyborohydride in dichloromethane to providecompounds of Formula (42). Compounds of Formula (42) can be reduced tocompounds of Formula (43) using a reducing agent such as but not limitedto lithium aluminum hydride in a solvent such as but not limited totetrahydrofuran. Compounds of Formula (43) can be used as described inScheme 9 wherein CH₂R³⁷ is as shown in Formula (43).

Compounds of Formula (43), which are representative of compounds ofFormula (1), can be prepared as shown in SCHEME 12. Compounds of Formula(39), wherein L is R¹, OR¹, or NHR¹; and A¹, E¹, Y¹, and D¹ are asdescribed herein, can be reacted with di-tert-butyl.diisopropylphosphoramidite and tetrazole to provide compounds of Formula(40). The reaction is typically performed in a solvent such as but notlimited to tetrahydrofuran, at a low temperature before warming to roomtemperature. Hydrogen peroxide can be added directly to the reactionmixture to provide compounds of Formula (41). The reaction is typicallyperformed at room temperature. Compounds of Formula (41) can be coupledwith compounds of Formula (41), wherein R⁵⁰ is as described herein,using coupling conditions known by those skilled in the art and widelyavailable in the literature to provide compounds of Formula (42).Compounds of Formula (42) can be reacted with an acid, such as but notlimited to trifluoroacetic acid, to provide compounds of Formula (43),which are representative of compounds of this invention. The reaction istypically performed in a solvent such as but not limited todichloromethane.

Compounds of Formula (46), which are representative of compounds orformula (III), can be prepared as shown in SCHEME 13. Compounds ofFormulas (44), wherein A¹, B¹, E¹, Y¹, D¹, and R²⁰ are as describedherein, can be treated with di-tert-butyl chloromethyl phosphate in thepresence of a base such as but not limited to N,N-diisopropylethylamine,to provide compounds of Formula (45) and Formula (45A). The reaction istypically performed at elevated temperatures, optionally using amicrowave oven, its a solvent such as but not limited todichloromethane. Compounds of Formula (45) can be reacted with an acid,such as but not limited to trifluoroacetic acid, to provide compounds ofFormula (46), which are representative of compounds of this invention.The reaction is typically performed in a solvent such as but not limitedto dichloromethane.

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACD/ChemSketch Version 12.01 (May 13, 2009), AdvancedChemistry Development Inc. Toronto, Ontario), or ChemDraw® Ver.9.0.5(CambridgeSoft, Cambridge, Mass.). Intermediates were named usingChemDraw® Ver. 9.0.5(CambridgeSoft, Cambridge, Mass.).

EXAMPLE 1

-   :5-[5(4-:[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-:[(4-:[(trans-4-methoxycyclohexyl)methyl]amino)-3-nitrophenyl)sulfonyl]carbamoyl)    phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl) methyl dihydrogen phosphate

EXAMPLE 1A

-   methyl    4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of NaH (pre-washed with hexane 17 g) in dichloromethane(700 mL) was added 5,5dimethyl-2-methoxycarbonylcyclohexanone (38.5 g)dropwise at 0° C. After stirring for 30 minutes, the mixture was cooledto −78° C. and trifluoroacetic anhydride (40 mL) was added. The reactionmixture was warmed to room temperature and stirred for 24 hours. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to provide the title compound.

EXAMPLE 1B

-   methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 1A (62.15 g), 4-chlorophenylboronic acid (32.24 g). CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Ether (4×200 mL) was added and the mixturewas filtered. The combined ether solution was concentrated to give theproduct.

EXAMPLE 1C

-   (2-(4-chlorophenyl)-4,4-dimethylcyclohexl-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 1B (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted withether (3×100 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography, elutingwith 0-30% ethyl acetate in hexanes to provide the title compound.

EXAMPLE 1D

-   tert-butyl    4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

Methanesulfonyl chloride (7.5 mL) was added via syringe to EXAMPLE 1C(29.3 g) and triethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0 C. and themixture was stirred for 1 minute, N-t-butoxycarbonylpiperazine (25 g)was added and the mixture was stirred at room temperature for 24 hours.The suspension was washed with brine, dried, (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography, elutingwith 10-20% ethyl acetate in hexanes to provide the title compound.

EXAMPLE 1E

-   1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

EXAMPLE 1D (200 mg) and triethylsilane (1 mL) were stirred indichloromethane (15 mL) and trifluoroacetic acid (15 mL) for 1 hour. Themixture was concentrated, taken up in ethyl acetate, washed twice withaqueous NaH₂PO₄, and brine, and dried (Na₂SO₄), filtered andconcentrated to provide the title compound.

EXAMPLE 1F

-   5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine(15.4 g) intetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide intetrahydrofuran (86 mL), and after 10 minutes, triisopropylchlorosilane(18.2 mL) was added. The mixture was stirred at room temperature for 24hours. The reaction was diluted with ether, and the resulting solutionwas washed twice with water.

The extracts were dried (Na₂SO₄), filtered, and concentrated. Theresidue was purified by flash chromatography, eluting with 10% ethylacetate in hexanes to provide the title compound.

EXAMPLE 1G

-   1-(triisopropylsiyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

To a mixture of EXAMPLE 1F (24.3 g) in tetrahydrofuran (500 mL) at −78°C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5mL) was added, and the mixture was allowed to warm to room temperatureover 1 hour. The reaction was poured into water, extracted thee timeswith ethyl acetate, and the combined extracts were washed with brine andconcentrated. The crude product was taken up in tetrahydrofuran (200 mL)at 0° C., and 1M NaOH (69 mL) was added, followed by 30% H₂O₂ (8.43 mL),and the solution was stirred for 1 hour. Na₂S₂O₃ (10 g) was added, andthe pH was adjusted to 4-5 with concentrated HCl and solid NaH₂PO₄. Thesolution was extracted twice with ethyl acetate, and the combinedextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography, elutingwith 5-25% ethyl acetate in hexanes to provide the title compound.

EXAMPLE 1H

-   methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate

A mixture of EXAMPLE 1G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g),and K₃PO₄ (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24hours. The reaction was cooled, diluted with ether (600 mL), and washedtwice with water, and brine, and concentrated. The residue was purifiedby flash choromatography, eluting with 2-50% ethyl acetate in hexanes toprovide the title compound.

EXAMPLE 1I

-   methyl    2-(1H-pyrrolo[2,3b]pyridin-5-yloxy)-4-(4-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

A mixture of EXAMPLE 1H (1.55 g), EXAMPLE 1E (2.42 g), and HK₂PO₄ (1.42g) in dimethylsulfoxide (20 mL) at 135° C. was stirred for 24 hours. Thereaction was cooled, diluted with ether (400 mL), and washed three timeswith 1 M aqueous NaOH, and brine, and concentrated. The residue waspurified by flash chromatography, eluting with 10-50% ethyl acetate inhexanes to provide the title compound.

EXAMPLE 1J

-   2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((1-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic    acid

EXAMPLE 1I (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50° C. wasstirred for 24 hours. The reaction was cooled, added to aqueous NaH₂PO₄solution, and extracted three times with ethyl acetate. The combinedextracts were washed with brine, and concentrated to give the titleproduct.

EXAMPLE 1K

-   (4-methoxycyclohexyl)methanamine

(4-Methoxyphenyl)methanamine (1.0 g) in ethanol (10 ml) was treated with5% Rh—Al₂O₃ (99.8 mg, 0.048 mmol) under H₂ atmosphere (500 psi) at 50°C. for 16 hours. Additional 5% Rh-Al₂O₃ (0.4 g) was added. The resultingmixture was stirred under H₂ atmosphere (500 psi) at 60° C. for 2 hours.The insoluble material was filtered off and the filtrate wasconcentrated to provide a mixture of cis and trans product as an oil,which was used in the next step without further purification.

EXAMPLE 1L

-   Trans-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE 1K (1 g) intetrahydrofuran (20 mL) was treated with N,N-diisopropylethylamine(0.871 mL) overnight. The reaction mixture was concentrated and theresidue was purified by reverse phase chromatography, eluting with40-55% acetonitrile in 0.1% trifluoroacetic acid in water over 25minutes.

EXAMPLE 1M

-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)    methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

A mixture of EXAMPLE 1L (35 mg), EXAMPLE 1J (53 mg),4-dimethylaminopyridine (46 mg) and1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (21.5 mg)in dichloromethane was stirred overnight and concentrated. The residuewas purified by reverse phase HPLC, eluting with 40% -70% acetonitrilein 0.1% trifluoroacetic acid water over 40 minutes. The desiredfractions were concentrated to remove acetonitrile, neutralized withNaHCO₃ and extracted with dichloromethane. The organic layer was driedover Na₂SO₄, filtered, concentrated and dried to provide the titlecompound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆)δ 11.69 (s, 1 H), 11.37(s, 1H), 8.52-8.62 (m, 2 H), 8.04 (d, 1 H), 7.79 (dd, 1 H), 7.47-7.55(m, 3 H), 7.34 (d, 2 H), 7.02-7.09 (m, 3 H), 6.68 (dd, 1 H), 6.39 (dd, 1H), 6.19 (d, 1 H), 3.21-3.27 (m, 5 H), 3.02-3.12 (m, 5 H), 2.75 (s, 2H), 2.20 (s, 4 H), 2.14 (s, 2 H), 1.93-2.04 (m, 4 H), 1.79 (d, 2 H),1.55-1.65 (m, 1H), 1.38 (t, 2H), 0.97-1.12 (m, 4 H), 0.92 (s, 6 H).

EXAMPLE 1N

-   {5-]5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[(4-{[(trans-4-    methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl)carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl}methyl    dihydrogen phosphate

To a solution of EXAMPLE 1M (1.2 g) in acetonitrile (20 mL) was addeddi-tert-butyl chloromethyl phosphate (1.1 g) andN,N-diisopropylethylamine (1.2 mL). The mixture was heated in a Biotagemicrowave synthesizer as 80 C. for 1.5 hours and concentrated. Theresidue was dissolved in dichloromethane (5 ml), treated withtrifluoroacetic acid (5 ml) for 1 hour and concentrated. The residue waspurified by reverse phase chromatography, and was eluted with 40% -65%acetonitrile in 0.1% trifluoroacetic acid water to give the titlecompound as a trifluotoacetic acid salt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.73 (d, 1 H), 8.60 (t, 1 H), 8.53 (d, 1 H), 8.46 (d, 1 H), 7.98 (d, 1H), 7.81 (dd, 1 H), 7.5 (d, 1 H), 7.40 (d, 2 H), 7.15 (d, 1 H), 7.09 (d,2 H), 6.85 (d, 1 H), 6.79 (dd. 1 H). 6.46 (d, 1 H), 6.25 (d, 2 H), 3.28(m, 4 H), 3.22 (s, 3 H), 3.03 (m, 3 H), 2.25 (m, 3 H), 2.01 (m, 5 H),1.78 (m, 3 H), 1.61 (m, 2 H), 1.46 (m, 4 H), 1.03 (m, 6 H) 0.95 (s, 6H).

EXAMPLE 2

-   (5-{5-(4-(|2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl|piperazin-1-yl)-2-[(|3-nitro-4-[(tetrahyro-2H-pyran-    4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy-}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyl    dihydrogen phosphate

EXAMPLE 2A

-   3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

A mixture of 4-fluoro-3-mirobenzenesulfonamide (2.18 g),1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) intetrahydrofuran (30 ml) were stirred overnight, neutralized withconcentrated HCl and concentrated. The residue was suspended in ethylacetate and the precipitates were collected, washed with water and driedto provide the title compound.

EXAMPLE 2B

-   4-(4-|[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl|methyl|piperazin-1-yl)-N-(|3-nitro-4-[(tetrahydro-2H-pyran-4-

ylmethy)amino]phenyl|sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

EXAMPLE 1J (3.39 g), EXAMPLE 2A (1.87 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodimide hydrochloride (2.39 g),and 4-dimethylaminopyridine (1.09 g) were stirrer in CH₂CL₂ (40 ml) for24 hours. The residue was purified by flash chromatography, eluting with25-100% ethyl acetate in hexanes, then 10% methanol in ethyl acetatewith 1% acetic acid to give the product as a white solid. ¹H NMR (300MHz, dimethysulfoxide-d₆) 11.65 (brs, 1H). 8.55 (brs, 1H), 8.04 (d, 1H,7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d, 2H),6.68 (dd, 1H),6.39(d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m, 4H),3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd, 2H),1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).

EXAMPLE 2C

-   (5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(|3-nitro-4-[(tetrahydro-2H-    pyran-4-ylmethyl)amino]phenyl|sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7yl)methyl    dihydrogen phosphate

The title compound was prepared according to the procedure described inEXAMPLE 1N by substituting EXAMPLE 1M with EXAMPLE 2B. ¹H NMR (300 MHz,DMSO-D₆)δ ppm 8.72 (d, 1 H), 8.61 (t, 1 H), 8.53 (t, 1 H), 8.46 (d, 1H), 7.98 (d, 1 H), 7.82 (dd, 1 H), 7.57 (d, 1 H), 7.39 (d, 2 H), 7.19(d, 1 H), 7.09 (d, 2 H), 6.84 (d, 1 H), 6.79 (dd, 1 H) 6.46 (d, 1 H),6.25 (d, 2 H), 3.85 (m, 6 H). 3.29 (m, 8 H), 2.23 (m, 3 H), 2.03 (m, 2H), 1.89 (m, 2H), 1.62 (t, 3 H), 1.46 (m, 2 H), 1.27 (m, 3H), 0.95 (s, 6H).

EXAMPLE 3

-   (5-{5-{[4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(    {4-[(4-fluorotetrahydro-2H-pyran-4-    yl)methoxy]-3-nitrophenyl}sulfonyl)carbamoyl]phenoxy{-7H    -pyrrolo[2,3-b]pyridin-7-yl)methyl dihydrogen phosphate

EXAMPLE 3A

-   1,6-dioxaspiro[2.5]octane-2-carbonitrile

A mixture of tetrahydropyran-4-one (10 mL) and chloryacetonitrile (6.4mL) in tert-butanol (10 mL) was stirred for 10 minutes. To this solutionwas added a solution of potassium tert-butoxide (12.11 g) in 200 mL oftert-butanol at room temperature over 40 minutes. The reaction mixturewas stirred for 16 hours, diluted with water and quenched slowly with 1N aqueous HCl. The solvent was partially removed by rotary evaporation.It was then extracted with ether (5× 200 mL). The combined extracts waswashed with brine, dried over MgSO₄, filtered, and the filtrate wasconcentrated and purified by flash chomatography on silica with 3:7 to1.1 ethyl acetate:hexanes to provide the title compound.

EXAMPLE 3B

-   2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile

EXAMPLE 3A (11.5 g) in dichloromethane (40 mL) in a polypropylene bottlewas treated with 70% hydrogen fluoride-pyridine (10.4 mL) dropwise at 0°C. The solution was allowed to warm to room temperature over 3 hours,and stirred for an additional 1.5 hours. The reaction mixture wasdiluted with ethyl acetate (200 mL) and poured into saturated aqueousNaHCO₃. Additional solid NaHCO₃ was used carefully until bubblingceased. The organic layer was isolated, and the aqueous layer wasextracted with additional ethyl acetate three times (150 mL each). Thecombined organic layers were washed with 5% HCl (50 mL each, twice),brine, dried over MgSO₄, filtered and concentrated to give the desiredproduct which was used directly in the next step.

EXAMPLE 3C

-   (4-fluorotetrahydro-2H-pyran-4-yl)methanol

EXAMPLE 3B (11.7 g, 74 mmol) in 2-propanol (150 mL) and water (37.5 mL)was cooled to 0° C. To this solution was added NaBH₄(4.20 g, 111 mmol).The solution was stirred and allowed to warm to room temperature over 3hours. It was quenched with acetone, and stirred for another 1 hour. Theclear liquid was separated from solid by decanting. Additional ethylacetate (2×100 mL) was used to wash the solid, and the mixture wasdecanted. The combined organic solutions were concentrated. The residuewas purified by flash chomatography, eluting with 1:1 ethylacetate:hexanes to provide the title compound.

EXAMPLE 3D

-   4((4-fluorotetrahydro-2H-pyran-4-ylmethoxy)-3-nitrobenzenesulfonamide

EXAMPLE 3C (2.0 g) and 4-fluoro-3nitrobenzenesulfonamide (2.84 g) intetrahydrofuran (30 mL) was treated with 60% NaH (1.377 g) overnight.The mixture was poured into water, neutralized with 10% HCl, andextracted with ethyl acetate thee times. The combined organic layerswere washed with brine, dried ever MgSO₄, filtered, and concentrated.The residue was triturated with a mixture of ethyl acetate and hexane toprovide the title compound.

EXAMPLE 3E

-   4-(4-{[2-(4-chlorophenyl-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared according to the procedures described inEXAMPLE 1M by substituting EXAMPLE 1L with EXAMPLE 3D. ¹H NMR(dimethylsulfoxide-d₆). 11.64 (s, 2H), 8.33 (s, 1H), 8.00-8.01 (m, 2H)7.39-7.57 (m, 4H), 7.33 (d, J=8.24 Hz, 2H), 7.03 (d, J=8.54 Hz, 2H),6.65 (dd, J=9, 1.98 Hz, 1H), 6.37-6.38 (m, 1H), 6.19 (d, J=1.53 Hz. 1H),4.35 (d, J=20.75 Hz, 2H), 3.74-5.78 (m, 2H), 3.55-3.60 (m, 2H), 3.07(br, 4H), 2.80 (br, 2H), 2.25 (br. 4H), 2.13 (br, 2H), 1.81-1.94 (m,6H), 1.38 (t, J=6.26 Hz, 2H), 0.91 (s, 6H).

EXAMPLE 3F

-   (5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1    -yl]methyl}piperazin-1-yl)-2-[({4-[(4-fluorotetrahydro-2H-    pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyl    dihydrogen phosphate

The title compound was prepared according to the procedures described inEXAMPLE 1N by substituting EXAMPLE 1M with EXAMPLE 3E. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.72 (d, 1H) 8.43 (d, 1H), 8.36 (d, 1H), 8.09(dd, 1H),7.95 (d, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.09 (d, 2H),6.84 (d, 1H), 6.80 (dd, 1H), 6.49 (d, 1H), 6.25 (d, 2 H), 4.42 (d, 3H),3.79 m, 6 H), 2.21 (m, 3H), 2.03 (s, 3H), 1.85 (m, 6H), 1.46 (t, 2H),0.95 (s, 6H).

EXAMPLE 4

-   3-[(4-|([4-|(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-    yloxy)benzoyl]sulfamoyl|-2-nitrophenyl)amino]-2,2-dimethylpropyl    dihydrogen phosphate

EXAMPLE 4A

-   4-(3-hydroxy-2,2-dimethylpropylamino)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 2A using3-amino-2,2-dimethylpropan-1-ol in place of(tetrahydro-2H-pyran-4-yl)methanamine.

EXAMPLE 4B

-   di-tert-butyl 2.2-dimethyl-3-(2-nitro-4-sulfamoylphenylamino)propyl    phosphate

To a solution of EXAMPLE 4A (540 mg) in tetrahydrofuran (5 ml) was addeddi-tert-butyl diisopropylphosphoramidite (0.84 ml) and 0.45 M1H-tetrazole (7.91 ml) at 0° C. The mixture was stirred at roomtemperature for 1.5 hours and cooled to 0° C. 30% Hydrogen peroxide(0.82 ml) was added. The mixture was stirred at room temperature for 30minutes, ice water and sodium bisulfite (1.1 g) were added. Theresulting mixture was diluted with dichloromethane and the organic layerwas washed with water extensively until the water layer became pHneutral. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography, elutingwith 0-66% ethyl acetate in dichloromethane to provide the titlecompound.

EXAMPLE 4C

-   3-(4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-    yl)benzoyl)sulfamoyl)-2-nitrophenylamino)-2,2-dimethylpropyl    di-tert-butyl phosphate

The title compound was prepared as described in EXAMPLE 1M using EXAMPLE4B in place of EXAMPLE 1L.

EXAMPLE 4D

-   3-[(4-{[4-{]2-(4-chlorophenyl)-4,4-dimethylcyclohex-1    -en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-    yloxyl)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-dimethylpropyl    dihydrogen phosphate

EXAMPLE 4C (250 mg) in dichloromethane (25 ml) at 0° C. was treated withtrifluoroacetic acid (4 ml). The mixture was stirred at 0°C. for 30minutes and at room temperature for 1 hour and concentrated. The residuewas dissolved in acetonitrile and saturated NaHCO₃ was added until pH 9,followed by the addition of saturated Na₂CO₃ (0.5 ml). The mixture wasconcentrated, and the residue was purified by HPLC, and eluted with 30%-70% methanol in water to provide the title compound. ¹H NMR (400 MHz.DMSO-d₆)δ 8.41 (s, 1H). 8.21 (s, 1H), 7.83 (d, 1H), 7.52 (d, 1H),7.25-7.42 (m, 4H), 6.89-7.09 (m, 4H), 6.64 (s, b 1H), 6.29 (d, 1H), 6.08(d, 1H), 2.91-3.12 (m, 6H), 2.68-2.79 (m, 2H), 2.06-2.26 (m, 6 H),1.88-1.99 (m, 2H), 1.37 (s, 2H), 0.67-0.98 (m, 12H).

EXAMPLE 5

-   trans-4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenoxy)methyl]cyclohexyl    dihydrogen phosphate

EXAMPLE 5A

-   Trans-4-(4(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 3D by replacingEXAMPLE 3C with trans-(4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol(made according to the procedures in WO 2008/124878).

EXAMPLE 5B

-   4-((trans-4-hydroxycyclohexyl)methoxy)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 5A (630 mg) in methanol (5 ml) and dichloromethane(5 ml) was treated with concentrated HCl (1.5 ml) for 1 hour and themixture was concentrated. The residue was dried under vacuum to providethe title compound.

EXAMPLE 5C

-   di-tert-butyl trans-4-((2-nitro-4-sulfamoylphenoxy)methyl)cyclohexyl    phosphate

The title compound was prepared as described in EXAMPLE 4B using EXAMPLE5B in place of EXAMPLE 4A.

EXAMPLE 5D

-   Trans-4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-    yl)benzoyl)sulfamoyl)-2-nitrophenoxy)methyl)cyclohexyl di-tert-butyl    phosphate

The title compound was prepared as described its EXAMPLE 1M usingEXAMPLE 5C in place of EXAMPLE 1L.

EXAMPLE 5E

-   trans-4-[(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)    piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-    yloxy)benzoyl]sulfamoyl)2-nitrophenoxy)methyl]cyclohexyl dihydrogen    phosphate

The title compound was prepared as described in EXAMPLE 4D using EXAMPLE5D in place of EXAMPLE 4C. ¹H NMR (400 MHz, DMSO-d₀) δ ppm 11.61 (s, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.65-7.80 (m, 1H), 7.59 (d, 1 H),7.20-7.41 (m, 4 H), 6.97-7.08 (m, 3 H), 6.49-6.66 (m, 1 H), 6.21-6.30(m, 2 H), 3.73-3.97 (m, 2H), 2.98 (s, 4 H), 2.69 (d, 2 H), 2.14 (s, 7H), 1.94 (s, 2 H), 1.57-1.81 (m, 3 H), 1.37 (s, 2 H), 1.11 (d, 4 H),0.91 (s, 6 H).

EXAMPLE 6

-   4(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-2,2-dimethylpropyl)amino]-3-    nitrophenyl}sulfonyl)-2-(2-(1-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1M using EXAMPLE4A in place of EXAMPLE 1L. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ11.68 (s, 1H), 11.35 (s, 1H), 8.96 (t, 1H), 8.56 (d, 1H), 8.05 (d, 1H),7.79 (dd, 1H), 7.46-7.56 (m, 3H), 7.34 (d, 2H), 7.10 (d, 1H), 7.04 (d,2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1 H), 5.10 (t, 1H), 3.29 (d,1H), 3.24 (d, 1H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d, 6H), 1.95 (s,2H), 1.38 (s, 2H), 0.93 (d, 12H).

EXAMPLE 7

-   Trans-4-(4{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxycyclohexyl)methoxy]-3-    nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2.3-b]pyridin-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 1M using EXAMPLE5B in place of EXAMPLE 1L. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ11.69(s, 1H), 11.27 (s, 1H), 8.34 (d, 1H), 7.95-8.08 (m, 2H), 7.47-7.55(m, 3H), 7.32-7.40 (m, 3H), 7.01-7.07 (m, 2H), 6.68 (dd, 1H), 6.39 (dd.1H), 6.20 (d, 1H), 4.54 (d, 1H), 3.96-4.06 (m, 2H), 3.10 (s, 4H), 2.84(s, 2H), 2.05-2.39 (m, 6H), 1.96 (s, 2H), 1.46-1.93 (m, 2H), 1.39 (t,2H), 0.98-1.29 (m, 4H), 0.92 (s, 6H).

1-6. (canceled)
 7. A compound having Formula (Ia), Formula (IIa), orFormula (IIIa):

or a therapeutically acceptable salt thereof, wherein A¹ is C(A²); A² isH B¹ is OR¹ or NHR¹, wherein R¹ is alkyl substituted with R¹⁰: D¹ is H;E¹ is H; Y¹ is NO₂; G¹ is R^(1B), OR^(1B), or NHR^(1B), wherein R^(1B)is alkyl substituted with OP(O)(OH)(OH) or with C₃-C₁₀-cycloalkylsubstituted with OP(O)(OH)(OH); and R¹⁰ is C₃-C₁₀-cycloalkyl having oneor two CH₂ moieties unreplaced or replaced with O; wherein the moietyrepresented by R¹⁰ is unsubstituted or substituted with one or two orthree or four or five substituents independently selected from the groupconsisting of R⁵⁰, OR⁵⁰, F, Cl, Br or I; and R⁵⁰ is alkyl. 8-11.(canceled)
 12. A method of treating a cancer in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of the compound or therapeutically acceptable salt ofclaim
 7. 13. The method of claim 12, wherein the cancer is selected fromthe group consisting of bladder cancer, brain cancer, breast cancer,bone marrow cancer, cervical cancer, chronic lymphocytic leukemia,colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, and spleen cancer.
 14. The method of claim 12,wherein the cancer is acute lymphoblastic leukemia.
 15. The method ofclaim 12 further comprising administering to the patient atherapeutically effective amount of one additional therapeutic agent ormore than one additional therapeutic agent.
 16. The method of claim 12,wherein the compound or therapeutically acceptable salt administered tothe patient has Formula (Ia)

or a therapeutically acceptable salt thereof, wherein A¹ is C(A²); A² isH; D¹ is H; E¹ is H; Y¹ is NO²; and G¹ is R^(1B), OR^(1B), or NHR^(1B),wherein R^(1B) is alkyl substituted with C₃-C₁₀-cycloalkyl, which issubstituted with OP(O)(OH)(OH).
 17. The method of claim 16, wherein thecompound or therapeutically acceptable salt is a compound selected fromthe group consisting of:3-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-dimethylpropyldihydrogen phosphate; andtrans-4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenoxy)methyl]cyclohexyldihydrogen phosphate, or a therapeutically acceptable salt thereof. 18.The method of claim 12, wherein the compound or therapeuticallyacceptable salt administered to the patient has Formula (IIIa)

or a therapeutically acceptable salt thereof, wherein A¹ is C(A²); A² isH; B¹ is OR¹ or NHR¹, wherein R¹ is alkyl substituted with R¹⁰; D¹ is H;E¹ is H; Y¹ is NO₂; G¹ is R^(1B), wherein R^(1B) is alkyl substitutedwith OP(O)(OH)(OH); R¹⁰ is C₃-C₁₀-cycloalkyl having one or two CH₂moieties unreplaced or replaced with O; wherein the moiety representedby R10 is unsubstituted or substituted with one or two or three or fouror five substituents independently selected from the group consisting ofR⁵⁰, OR⁵⁰, F, Cl, Br or I; and R⁵⁰ is alkyl.
 19. The method of claim 18,wherein the compound or therapeutically acceptable salt is a compoundselected from the group consisting of:(5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate;{5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[(4-{[(trans-4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl}methyldihydrogen phosphate; and(5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyldihydrogen phosphate, or a therapeutically acceptable salt thereof. 20.A method of treating an autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of the compound or therapeutically acceptable salt of claim 7.